CN112004817A

CN112004817A - Macrocyclic compounds as modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions thereof, their use in the treatment of cystic fibrosis, and processes for their preparation

Info

Publication number: CN112004817A
Application number: CN201980025942.6A
Authority: CN
Inventors: J·J·克莱门斯; A·R·阿贝拉; C·D·安德森; B·B·布什; W·G·陈; T·克莱弗兰; T·R·库恩; B·弗里曼; S·G·吉尔梅; P·格鲁滕赫伊斯; A·V·古列维奇; S·S·哈迪达鲁亚; C·K-J·夏; P·康; H·哈图亚; J·麦卡特尼; M·T·米勒; P·帕拉塞利; F·皮埃尔; S·E·斯威夫特
Original assignee: Vertex Pharmaceuticals Inc
Current assignee: Vertex Pharmaceuticals Inc
Priority date: 2018-02-15
Filing date: 2019-02-14
Publication date: 2020-11-27
Anticipated expiration: 2039-02-14
Also published as: HUE061046T2; TWI780304B; JP2022126802A; PL3752510T3; CR20200403A; ES2939775T3; KR102482271B1; SG11202006614VA; JP7214743B2; US11866450B2; IL294042A; EP4198037A1; FI3752510T3; RS64018B1; MX2020008268A; CN112004817B; US20190248809A1; TW201938566A; PE20210454A1; AU2019222758B2

Abstract

Disclosed herein are compounds of formula (I), pharmaceutically acceptable salts thereof, deuterated derivatives of any of the foregoing, and metabolites of any of the foregoing. Also disclosed are pharmaceutical compositions comprising each of the above, methods of using each of the above to treat cystic fibrosis, and methods for making each of the above.

Description

Macrocyclic compounds as modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions thereof, their use in the treatment of cystic fibrosis, and processes for their preparation

This application claims priority to U.S. provisional application 62/631,453 filed on 2018, 2, 15, the disclosure of which is incorporated herein by reference in its entirety.

Disclosed herein are modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), pharmaceutical compositions containing the modulators, methods of treating Cystic Fibrosis, and methods for making the modulators.

Cystic Fibrosis (CF) is a recessive genetic disease affecting approximately 70,000 children and adults worldwide. Despite advances in the treatment of CF, there is no cure.

In patients with CF, mutations in the endogenously expressed CFTR in the respiratory epithelium result in reduced apical anion secretion, causing an imbalance in ionic and fluid transport. The resulting decrease in anion transport causes increased mucus accumulation in the lungs and concomitant microbial infection, ultimately leading to death in CF patients. In addition to respiratory diseases, CF patients often suffer from gastrointestinal problems and pancreatic insufficiency, which, if left untreated, can lead to death. In addition, most men with cystic fibrosis are infertile, and women with cystic fibrosis have reduced fertility.

Sequence analysis of the CFTR gene has revealed a number of causative mutations (Cutting, G.R. et al (1990) Nature 346: 366-. To date, more than 2000 mutations have been identified in the CF gene; currently, the CFTR2 database contains information on only 322 of these identified mutations with sufficient evidence to define 281 mutations as being pathogenic the most common pathogenic mutation is a deletion of the phenylalanine at position 508 of the CFTR amino acid sequence and is commonly referred to as the F508del mutation. This mutation occurs in approximately 70% of cases of cystic fibrosis and is associated with severe disease.

Deletion of residue 508 in CFTR prevents the nascent protein from folding correctly. This results in the mutant protein not being able to leave the Endoplasmic Reticulum (ER) and be transported to the plasma membrane therefore, the number of CFTR channels present in the membrane for anion transport is much smaller than that observed in cells expressing wild-type CFTR, i.e., CFTR has no mutation. (Quinton, P.M. (1990), FASEB J.4: 2709-2727.) although less functional than the wild-type CFTR channel, channels deficient by the F508del mutation remain functional (Dalemans et al (1991), Nature Lond.354: 526-528; Pasyk and Foskett (1995), J.cell.biochem.270: 12347-50.) in addition to F508del, other causative mutations of CFTR that result in defective migration, synthesis and/or channel gating can be up-or down-regulated to alter anion secretion and alter disease progression and/or severity.

CFTR is a cAMP/ATP-mediated anion channel expressed in a variety of cell types, including absorptive and secretory epithelial cells, where it regulates transmembrane anion flux, as well as the activity of other ion channels and proteins. In epithelial cells, proper functioning of CFTR is critical to maintaining electrolyte transport throughout the body, including respiratory and digestive tissues. CFTR consists of approximately 1480 amino acids encoding a protein consisting of tandem, repeating transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain.

Chloride transport through ENaC and CFTR present on apical membranes and Na expressed on the basolateral surface of cells⁺-K⁺ATP enzyme Pump and Cl^-Coordination activity of the channels occurs. Secondary active transport of chloride ions from the luminal side results in intracellular chloride ion accumulation, which can then pass through Cl^-The channel passively leaves the cell, causing vector transport. Na (Na)⁺/2Cl^-/K⁺Cotransporter, Na⁺-K⁺ATP-enzyme Pump and bottom outer Membrane K⁺Since water is never actively transported by itself, its flow across the epithelium depends on the slight transepithelial osmotic gradient created by the bulk flow of sodium and chloride.

Thus, there is a need for new treatments for CFTR mediated diseases.

Disclosed herein are novel compounds, including compounds of formulae (I), (II-a), (II-B), (III-a), (III-B), (IV-a), (IV-B), (IV-C), (V-a), (V-B), (VI-a), (VI-B), (VI-C), and (VI-D), pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing.

A pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing,

wherein:

-ring a is phenyl, a 5-membered heteroaryl ring or a 6-membered heteroaryl ring;

-ring B is a pyridyl ring;

-ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6-membered heterocyclyl ring, a 5-membered heteroaryl ring or a 6-membered heteroaryl ring;

x is O, NH or N (C)₁-C₄Alkyl groups);

each R¹Independently selected from C₁-C₂Alkyl radical, C₁-C₂Alkoxy radical, C₁-C₂Haloalkyl, C₁-C₂Haloalkoxy, halogen, cyano and hydroxy;

-m is 0, 1, 2, 3 or 4;

each R²Independently selected from C₁-C₂Alkyl radical, C₁-C₂Alkoxy radical, C₁-C₂Haloalkyl, C₁-C₂Haloalkoxy, halogen, cyano and hydroxy;

-n is 0, 1 or 2;

each R³Is methyl;

each R⁴Independently selected from the group consisting of halogen, oxo, hydroxy, cyano and- (Y)_k-R⁷A group, or optionally, two R⁴Together with the atoms to which they are attached form a 5-to 6-membered cycloalkyl or heterocyclyl ring optionally and independently substituted with one or more groups selected from: halogen, C₁-C₂Alkyl, haloalkyl, hydroxy, C₁-C₂Alkoxy and C₁-C₂A haloalkoxy group; wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

-each Y is independently selected from C (R)⁵)(R⁶) The radicals, -O-and-NR^a-group in which- (Y)_k-R⁷Wherein the heteroatom is not bound to- (Y)_k-R⁷Another hetero atom of (1)An atomic bond, wherein:

each R⁵And R⁶Independently selected from hydrogen, halogen, hydroxy, C ₁-C₄Alkyl and C_3-5Cycloalkyl radicals, or R on the same carbon⁵And R⁶Together form C_3-5Cycloalkyl or oxo;

-R⁵and R⁶Each optionally independently substituted with one or more groups selected from: c₁-C₂Alkyl radical, C₁-C₂Haloalkyl, halogen, hydroxy, C₁-C₂Alkoxy and C₁-C₂A haloalkoxy group; and is

Each R^aIndependently selected from hydrogen and C₁-C₂An alkyl group; and is

-R⁷Selected from hydrogen, halogen, cyano and C optionally substituted by one or more groups selected from₃-C₁₀Cycloalkyl groups: c₁-C₂Alkyl radical, C₁-C₂Haloalkyl and halogen;

-q is 1, 2, 3 or 4; and is

-Z is of formula (L)_rThe divalent linker of (1), wherein:

-r is 1, 2, 3, 4, 5 or 6;

-each L is independently selected from C (R)⁸)(R⁹) The radicals, -O-and-NR^b-a group wherein the heteroatom in Z is not bound to another heteroatom in Z, wherein:

each R⁸And R⁹Independently selected from hydrogen, halogen, C₁-C₂Haloalkyl, C₁-C₂Alkyl, hydroxy, C₁-C₂Alkoxy and C₁-C₂A haloalkoxy group; and is

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

In some embodiments, ring D in formula (I) is pyridin-2 (1H) -one, pyrrolidin-2-one, or imidazolidin-2-one.

Also disclosed are methods of treating cystic fibrosis, a CFTR-mediated disease, comprising administering to a subject in need thereof at least one of the novel compounds disclosed herein and/or at least one pharmaceutically acceptable salt thereof, optionally as part of a pharmaceutical composition comprising at least one additional component.

Also disclosed are methods of treating CFTR mediated diseases cystic fibrosis comprising administering at least one of the novel compounds disclosed herein and/or at least one pharmaceutically acceptable salt thereof, (R) -1- (2, 2-difluorobenzo [ d ] [1, 3] dioxol-5-yl) -N- (1- (2, 3-dihydroxypropyl) -6-fluoro-2- (1-hydroxy-2-methylpropan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide ((compound II) and N- [2, 4-bis (1, 1-dimethylethyl) -5-hydroxyphenyl ] -1, 4-dihydro-4-oxoquinoline-3-carboxamide ((compound III) to a patient in need thereof Optionally as part of at least one pharmaceutical composition comprising at least one additional component.

Drawings

Fig. 1 shows the structure of a non-limiting example of the novel compounds disclosed herein.

Fig. 2 is a representative list of CFTR mutations.

Definition of

As used herein, the term "alkyl" refers to a saturated aliphatic hydrocarbon (containing, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms). The alkyl group may be substituted or unsubstituted and branched or unbranched.

As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms.

As used herein, the term "cycloalkyl" refers to cyclic non-aromatic hydrocarbons containing from 3 to 12 carbons (such as from 3 to 10 carbons) in the ring. Cycloalkyl encompasses monocyclic, bicyclic, tricyclic, polycyclic, bridged, fused, and spiro rings, including mono-and dispirocyclic rings. Non-limiting examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, spiro [2.2] pentane and dispiro [2.0.2.1] heptane. Cycloalkyl groups may be substituted or unsubstituted.

The term "alkoxy" as used herein refers to an alkyl or cycloalkyl group covalently bonded to an oxygen atom.

As used herein, the term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms.

The term "heteroaryl ring" as used herein refers to an aromatic ring comprising at least one ring atom that is a heteroatom such as O, N or S.

As used herein, the term "heterocyclyl" refers to a non-aromatic hydrocarbon containing from 3 to 12 atoms (such as from 3 to 10 atoms) in the ring, including at least one ring atom that is a heteroatom such as O, N or S.

Examples of the protecting group for nitrogen include, for example, tert-butyl carbamate (Boc), benzyl (Bn), p-methoxybenzyl (PMB), Tetrahydropyranyl (THP), 9-fluorenylmethyl carbamate (Fmoc), benzyl carbamate (Cbz), methyl carbamate, ethyl carbamate, 2, 2, 2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), allyl carbamate (Aloc or Alloc), formamide, acetamide, benzamide, allylamine, trifluoroacetamide, triphenylmethylamine, benzylidene amine, and p-toluenesulfonamide. A comprehensive list of nitrogen protecting Groups can be found in Wuts, P.G.M. "Green's Protective Groups in Organic Synthesis: fifth Edition, "2014, John Wiley and Sons.

"substituted" (whether preceded by the term "optionally") indicates that at least one hydrogen of the "substituted" group is replaced with a substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position.

As used herein, "deuterated derivative" refers to the same chemical structure, but with one or more hydrogen atoms replaced with deuterium atoms.

As used herein, "CFTR" refers to the cystic fibrosis transmembrane conductance regulator.

As used herein, "mutation" may refer to a mutation of the CFTR gene or CFTR protein. "CFTR gene mutation" refers to a mutation of the CFTR gene, and "CFTR protein mutation" refers to a mutation of the CFTR protein. Genetic defects or mutations or alterations in nucleotides in a gene typically result in mutations or frameshifts in the CFTR protein translated from the gene.

The term "F508 del" refers to a mutant CFTR protein lacking the amino acid phenylalanine at position 508.

As used herein, a patient that is "homozygous" for a particular gene mutation has the same mutation on each allele.

As used herein, a patient who is "heterozygous" for a particular genetic mutation has this mutation on one allele and a different mutation on the other allele.

As used herein, the term "modulator" refers to a compound that increases the activity of a biological compound or molecule, such as a protein.

As used herein, the term "CFTR corrector" refers to a compound that facilitates the handling and transport of CFTR to increase the amount of CFTR on the surface of a cell. The compounds of formulae (I), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C) and (VI-D), compound II, compound IV and pharmaceutically acceptable salts thereof disclosed herein are CFTR correctors.

As used herein, the term "CFTR potentiator" refers to a compound that increases the channel activity of the CFTR protein located on the cell surface, thereby enhancing ion transport.

As used herein, the term "active pharmaceutical ingredient" ("API") refers to a biologically active compound.

As used herein, the term "pharmaceutically acceptable salt" refers to a salt form of a compound of the present disclosure, wherein the salt is non-toxic. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and inorganic and organic bases. Pharmaceutically acceptable salts are well known in the art, for example, S.M.Berge et al describe in detail pharmaceutically Sciences, 1977, 66, 1-19.

Amorphous solids are generally isotropic, i.e., exhibit similar properties in all directions and do not have a well-defined melting point. The broad peak is characteristic of an amorphous solid. For a comparison of XRPD of amorphous and crystalline materials, see US 2004/0006237.

As used herein, the term "substantially amorphous" refers to a solid material having little or no long-range order in its molecular positions-for example, a substantially amorphous material has less than 15% crystallinity (e.g., less than 10% crystallinity or less than 5% crystallinity).

As used herein, the term "dispersion" refers to a dispersion system in which one substance (the dispersed phase) is distributed throughout a second substance (the continuous phase or vehicle) in discrete units. Generally, the dispersed phase may be a solid, liquid or gas. For solid dispersions, both the dispersed and continuous phases are solid. In pharmaceutical applications, the solid dispersion may comprise a crystalline drug (dispersed phase) in an amorphous polymer (continuous phase); or alternatively, an amorphous drug (dispersed phase) in an amorphous polymer (continuous phase.) in some embodiments, a solid dispersion includes a polymer that constitutes the dispersed phase and a drug that constitutes the continuous phase.

The terms "patient" and "subject" are used interchangeably and refer to an animal including a human.

The precise amount of an effective dose will depend on The therapeutic objectives and will be determined by one of skill in The Art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

As used herein, the term "treating" and similar terms generally refers to the amelioration or lessening of the severity of CF or its symptoms in a subject. Increased growth, increased weight gain, decreased mucus in the lungs, improved pancreatic and/or liver function, reduced chest infections, and/or reduced coughing or shortness of breath in a subject. Amelioration of any of these symptoms, or lessening of their severity, can be readily assessed according to standard methods and techniques known in the art.

The term "in combination with," as used herein in reference to two or more compounds, agents or additional active pharmaceutical ingredients, refers to the administration of two or more compounds, agents or active pharmaceutical ingredients to a patient before, simultaneously with or after each other.

The terms "about" and "approximately," when used in conjunction with a dose, amount, or weight percentage of an ingredient of a composition or dosage form, includes the value of the specified dose, amount, or weight percentage or a range of that dose, amount, or weight percentage recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to the effect obtained from that specified dose, amount, or weight percentage.

One of ordinary skill in the art will recognize that when disclosing the amount of a "compound, or pharmaceutically acceptable salt thereof," the amount of the pharmaceutically acceptable salt form of the compound is an amount equivalent to the concentration of the free base of the compound it is noted that the amount of a compound, or pharmaceutically acceptable salt thereof, disclosed herein is based on its free base form, for example, "10 mg of at least one compound selected from a compound of formula (I) or a pharmaceutically acceptable salt thereof" includes 10mg of a compound of formula (I) and a concentration of a pharmaceutically acceptable salt of a compound of formula (I) equivalent to 10mg of a compound of formula (I).

Suitable pharmaceutically acceptable salts are, for example, those disclosed in s.m. berge et al j.pharmaceutical Sciences, 1977, 66, 1-19. For example, table 1 in the paper provides the following pharmaceutically acceptable salts:

table 1:

non-limiting examples of pharmaceutically acceptable salts derived from suitable acids include: salts formed from inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid; salts formed from organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid; non-limiting examples of pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, and salts thereof Camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate. Pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium and N⁺(C_1-4Alkyl radical)₄And (3) salt. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Other non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. Other suitable non-limiting examples of pharmaceutically acceptable salts include benzenesulfonate and glucosamine salts.

The precise amount of a desired pharmaceutical composition will vary from subject to subject depending on the species, age, and general condition of the subject, the severity of the disease, the particular agent, its mode of administration, and the like. The specific effective dosage level for any particular patient or organism will depend upon a variety of factors including the condition being treated and the severity of the condition; the activity of the particular compound employed; the specific composition used; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the particular compound employed; the duration of treatment; medicaments for use in combination or concomitantly with the specific compounds employed; and similar factors well known in the medical arts. As used herein, the term "patient" refers to an animal, such as a mammal and further such as a human.

In some embodiments, the disclosure also relates to methods of treatment using isotopically-labeled compounds of the foregoing compounds, having the same structure as disclosed herein, except that one or more atoms therein have been replaced (isotopically-labeled) by one or more atoms having an atomic mass or mass number different from the atomic mass or mass number of the atom typically naturally occurring. Examples of commercially available isotopes that are suitable for the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example each²H、³H、¹³C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F and³⁶Cl。

isotopically-labeled compounds and salts can be used in a number of advantageous ways, and can be adapted for use in pharmaceuticals and/or in various types of assays, such as substrate tissue distribution assays³H) And/or carbon-14 (¹⁴C) The labeled compounds are particularly useful in various types of assays, such as substrate tissue distribution assays, due to their relative simplicity of preparation and excellent detectability. E.g. relative to not²H-labelled compound, deuterium: (²H) In general, deuterium (D) is used as a therapeutic agent in comparison to the isotopically unlabeled compound²H) Isotopically labeled compounds and salts can generally be prepared by carrying out the examples section and examples of the text of the present invention The synthetic schemes and procedures disclosed in the related descriptions in the preparations section were prepared by replacing the non-isotopically labeled reactants with readily available isotopically labeled reactants.

In some embodiments, the isotopically labeled compounds and salts are deuterium (g)²H) Labeled compounds and salts. In some embodiments, the isotopically labeled compounds and salts are derivatized with deuterium (ll), (ll²H) In the chemical structure, deuterium is represented as "²H "or" D ".

Deuterium (1)²H) The exchange of heavier isotopes generally reduces the ground state energy of chemical bonds and thus leads to a reduction in rate-limiting bond cleavage if bond cleavage occurs in or near saddle point regions along the multi-product reaction coordinates. If deuterium is bound to a carbon atom in an unalterable position, k_M/k_DSee s.l. harbeson and r.d. tung, Deuterium In Drug Discovery and Development, ann.rep.med.chem.2011, 46, 403-; and t.g.gate "Using the material in drug discovery: leaving the label in the drug "j.med. chem.2014, 57, 3595-.

The concentration of an isotope (e.g., deuterium) incorporated into isotopically labeled compounds and salts of the present disclosure can be defined by the isotopic enrichment factor. In some embodiments, if a substituent in a compound of the present disclosure is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

In the discovery and development of therapeutic agents, one skilled in the art has attempted to optimize pharmacokinetic parameters while retaining desirable in vitro properties.

One of ordinary skill in the art will appreciate that deuteration at one or more metabolically unstable sites on a compound or active metabolite can contribute to an improvement in one or more superior DMPK properties while maintaining biological activity as compared to the corresponding hydrogen analog.

In some embodiments, the present disclosure includes deuterated derivatives of the novel compounds disclosed herein, as well as pharmaceutically acceptable salts thereof. Non-limiting examples of deuterated compounds are disclosed in figure 1.

Each of the compounds described herein, including the compounds of formulas (I), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), and (VI-D), the compound II, the compound III, and the compound IV, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing, may be independently administered once daily, twice daily, or three times daily In some embodiments, at least one compound selected from the group consisting of compounds of formulas (I), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), and (VI-D), and pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing, is administered twice daily, hi some embodiments, at least one compound selected from compound II and pharmaceutically acceptable salts thereof is administered once daily. In some embodiments, at least one compound selected from compound II and pharmaceutically acceptable salts thereof is administered twice daily. In some embodiments, at least one compound selected from compound IV and pharmaceutically acceptable salts thereof is administered once daily. In some embodiments, at least one compound selected from compound IV and pharmaceutically acceptable salts thereof is administered twice daily. In some embodiments, deuterated derivatives of compounds II, III, and/or IV, or pharmaceutically acceptable salts thereof, are used in any of these embodiments.

In some embodiments, 10mg to 1,500mg of a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a deuterated derivative of said compound or salt is administered per day.

As set forth above, disclosed herein are compounds of formula (I):

a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the foregoing,

wherein:

-ring B is a pyridyl ring;

-X is O, NH or N (C1-C4 alkyl);

each R¹Independently selected from C₁-C₂Alkyl, aryl, heteroaryl, and heteroaryl,C₁-C₂Alkoxy radical, C₁-C₂Haloalkyl, C₁-C₂Haloalkoxy, halogen, cyano and hydroxy;

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

each R⁴Independently selected from the group consisting of halogen, oxo, hydroxy, cyano and- (Y)_k-R⁷A group, or optionally, two R⁴Together with the atoms to which they are attached form a 5-to 6-membered cycloalkyl or heterocyclyl ring optionally and independently substituted with one or more groups selected from: halogen, C ₁-C₂Alkyl, haloalkyl, hydroxy, C₁-C₂Alkoxy and C₁-C₂A haloalkoxy group; wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

-each Y is independently selected from C (R)⁵)(R⁶) The radicals, -O-and-NR^a-group in which- (Y)_k-R⁷Wherein the heteroatom is not bound to- (Y)_k-R⁷Wherein:

each R⁵And R⁶Independently selected from hydrogen, halogen, hydroxy, C₁-C₄Alkyl and C_3-5Cycloalkyl radicals, or R on the same carbon⁵And R⁶Together form C_3-5Cycloalkyl or oxo;

Each R^aIndependent of each otherIs selected from hydrogen and C₁-C₂An alkyl group; and is

-q is 1, 2, 3 or 4; and is

-Z is of formula (L)_rThe divalent linker of (1), wherein:

-r is 1, 2, 3, 4, 5 or 6;

each R⁸And R⁹Independently selected from hydrogen, halogen, C₁-C₂Haloalkyl, C₁-C₂Alkyl, hydroxy, C ₁-C₂Alkoxy and C₁-C₂A haloalkoxy group; and is

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

In some embodiments, the compound of formula I is a compound of formula (II-A) or (II-B):

wherein:

-the carbon represented by has S-stereochemistry or R-stereochemistry;

-ring B is a pyridyl ring;

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

each R⁴Independently selected from the group consisting of halogen, hydroxy, oxo, cyano and- (Y)_k-R⁷A group, or optionally, two R⁴Together with the atoms to which they are attached form a 5-to 6-membered cycloalkyl or heterocyclyl ring optionally and independently substituted with one or more groups selected from: halogen, C₁-C₂Alkyl, haloalkyl, hydroxy, C ₁-C₂Alkoxy and C₁-C₂Haloalkoxy, wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

Each R^aIndependently selectFrom hydrogen and C₁-C₂An alkyl group; and is

-q is 1, 2, 3 or 4;

-Z is of formula (L)_rThe divalent linker of (1), wherein:

-r is 1, 2, 3, 4, 5 or 6;

each R⁸And R⁹Independently selected from hydrogen, halogen, C₁-C₂Alkyl radical, C₁-C₂Haloalkyl, hydroxy, C₁-C₂Alkoxy and C₁-C₂A haloalkoxy group; and is

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

In some embodiments, the compound of formula I is a compound of formula (III-A) or (III-B):

wherein:

-the carbon represented by has S-stereochemistry or R-stereochemistry;

-ring B is a pyridyl ring;

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

each R⁴Independently selected from the group consisting of halogen, oxo, hydroxy, cyano and- (Y)_k-R⁷A group, or optionally, two R⁴Together with the atoms to which they are attached form a 5-to 6-membered cycloalkyl or heterocyclyl ring optionally and independently substituted with one or more groups selected from: halogen, C₁-C₂Alkyl, haloalkyl, hydroxy, C₁-C₂Alkoxy and C₁-C₂Haloalkoxy, wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

Each R^aIndependently selected from hydrogen andC₁-C₂an alkyl group; and is

-q is 1 or 2;

-Z is of formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Independently selected from hydrogen, halogen, C₁-C₂Alkyl, hydroxy, C₁-C₂Alkoxy and C₁-C₂A haloalkoxy group; and is

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

In some embodiments, the compound of formula I is a compound of formula IV-a:

wherein:

-the carbon represented by has S-stereochemistry or R-stereochemistry;

x is O, NH or N (C)₁-C₄Alkyl groups);

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

-k is 0, 1, 2, 3, 4, 5 or 6;

-R⁷Selected from hydrogen, halogen, cyano and optionally substituted by one or moreC substituted by a group selected from₃-C₁₀Cycloalkyl groups: c₁-C₂Alkyl radical, C₁-C₂Haloalkyl and halogen;

-q is 1 or 2;

-Z is of formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

In some embodiments, the compound of formula I is a compound of formula IV-B:

wherein:

-the carbon represented by has S-stereochemistry or R-stereochemistry;

-m is 0, 1, 2, 3 or 4;

each R²Independently selected from C₁-C₂Alkyl radical, C₁-C₂Alkoxy radical, C₁-C₂Haloalkyl group、C₁-C₂Haloalkoxy, halogen, cyano and hydroxy;

-n is 0, 1 or 2;

each R³Is methyl;

-k is 0, 1, 2, 3, 4, 5 or 6;

-R⁵and R⁶Each optionally independently substituted with one or more groups selected from: c ₁-C₂Alkyl radical, C₁-C₂Haloalkyl, halogen, hydroxy, C₁-C₂Alkoxy and C₁-C₂A haloalkoxy group; and is

-q is 1 or 2;

-r is 3 or 4;

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

In some embodiments, the compound of formula I is a compound of formula IV-C:

wherein:

-the carbon represented by has S-stereochemistry or R-stereochemistry;

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

each R⁴Independently selected from the group consisting of halogen, oxo, hydroxy, cyano and- (Y)_k-R⁷A group, or optionally, two R⁴Together with the atoms to which they are attached form a 5-to 6-membered cycloalkyl or heterocyclyl ring optionally and independently substituted with one or more groups selected from: halogen, C ₁-C₂Alkyl, haloalkyl, hydroxy, C₁-C₂Alkoxy and C₁-C₂Haloalkoxy, wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

-q is 1 or 2;

-r is 3 or 4;

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

In some embodiments, the compound of formula I is a compound of formula V-a:

Wherein:

-the carbon represented by has S-stereochemistry or R-stereochemistry;

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

-k is 0, 1, 2, 3, 4, 5 or 6;

each R⁵And R⁶Independently selected from hydrogen, halogen, hydroxy, C₁-C₄Alkyl and C_3-5Cycloalkyl radicals, orR on the same carbon ⁵And R⁶Together form C_3-5Cycloalkyl or oxo;

-q is 1 or 2;

-Z is of formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

In some embodiments, the compound of formula I is a compound of formula V-B:

wherein:

-the carbon represented by has S-stereochemistry or R-stereochemistry;

each R ¹Independently selected from C₁-C₂Alkyl radical, C₁-C₂Alkoxy radical, C₁-C₂Haloalkyl, C₁-C₂Haloalkoxy, halogen, cyano and hydroxy;

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

-k is 0, 1, 2, 3, 4, 5 or 6;

-R⁵and R⁶Each optionally independently substituted with one or more groups selected from: c₁-C₂Alkyl radical, C₁-C₂Haloalkyl, halogen, hydroxy, C ₁-C₂Alkoxy and C₁-C₂A haloalkoxy group; and is

-q is 1 or 2;

-r is 3, 4 or 5; and is

Each R⁸And R⁹Independently selected from hydrogen, halogen, C₁-C₂Alkyl, hydroxy, C₁-C₂Alkoxy and C₁-C₂A haloalkoxy group.

In some embodiments, the compound of formula I is a compound of formula VI-A or VI-B:

wherein:

-the carbon represented by has S-stereochemistry or R-stereochemistry;

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

each R⁴Independently selected from the group consisting of halogen, oxo, hydroxy, cyano and- (Y)_k-R⁷A group, or optionally, two R ⁴Together with the atoms to which they are attached form a 5-to 6-membered cycloalkyl or heterocyclyl ring optionally and independently substituted with one or more groups selected from: halogen, C₁-C₂Alkyl, haloalkyl, hydroxy, C₁-C₂Alkoxy and C₁-C₂Haloalkoxy, wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

-q is 1 or 2;

-Z is of formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

In some embodiments, the compound of formula I is a compound of formula VI-C or VI-D:

wherein:

-the carbon represented by has S-stereochemistry or R-stereochemistry;

x is O, NH or N (C)₁-C₄Alkyl groups);

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

each R⁴Independently selected from the group consisting of halogen, oxo, hydroxy, cyano and- (Y)_k-R⁷A group, or optionally, two R⁴Together with the atoms to which they are attached form a 5-to 6-membered cycloalkyl or heterocyclyl ring optionally and independently substituted with one or more groups selected from: halogen, C₁-C₂Alkyl, haloalkyl, hydroxy, C ₁-C₂Alkoxy and C₁-C₂Haloalkoxy, wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

-q is 1 or 2;

-r is 3 or 4; and is

Each R⁸And R⁹Independently selected from hydrogenHalogen, C₁-C₂Alkyl, hydroxy, C₁-C₂Alkoxy and C₁-C₂A haloalkoxy group.

Also disclosed herein are compounds having a structural formula selected from any one of the structural formulas depicted in figure 1, and pharmaceutically acceptable salts thereof.

In some embodiments, at least one compound selected from the novel compounds disclosed herein, pharmaceutically acceptable salts thereof, and deuterated derivatives of the foregoing is administered in combination with at least one compound selected from compound II, pharmaceutically acceptable salts thereof, and deuterated derivatives of the foregoing. In some embodiments, at least one compound selected from the novel compounds disclosed herein, pharmaceutically acceptable salts thereof, and deuterated derivatives of the foregoing is administered in combination with at least one compound selected from compound III, and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound selected from the novel compounds disclosed herein, pharmaceutically acceptable salts thereof, and deuterated derivatives of the foregoing is administered in combination with compound II, or pharmaceutically acceptable salts thereof, or deuterated derivatives of the foregoing, and at least one compound selected from compound III, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing.

In some embodiments, at least one novel compound (and/or at least one pharmaceutically acceptable salt thereof and/or at least one deuterated derivative of such compound or salt) may be administered in combination with at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is selected from:

(a) compound II:

and pharmaceutically acceptable salts thereof.

The chemical name of compound II is (R) -1- (2, 2-difluorobenzo [ d ] [1, 3] dioxol-5-yl) -N- (1- (2, 3-dihydroxypropyl) -6-fluoro-2- (1-hydroxy-2-methylpropan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide;

(b) compound III:

and pharmaceutically acceptable salts thereof.

The chemical name of compound III is N- (5-hydroxy-2, 4-di-tert-butyl-phenyl) -4-oxo-1H-quinoline-3-carboxamide; and

(c) compound IV:

and pharmaceutically acceptable salts thereof.

The chemical name of compound IV is 3- (6- (1- (2, 2-difluorobenzo [ d ] [1, 3] dioxol-5-yl) cyclopropane-1-carboxamido) -3-methylpyridin-2-yl) benzoic acid. In some embodiments, the compound of formula (I) and/or a pharmaceutically acceptable salt thereof may be administered in combination with compound II and/or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) and/or a pharmaceutically acceptable salt thereof can be administered in combination with compound III and/or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) and/or a pharmaceutically acceptable salt thereof may be administered in combination with compound IV and/or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) and/or a pharmaceutically acceptable salt thereof can be administered in combination with compound II and/or a pharmaceutically acceptable salt thereof and compound III and/or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) and/or a pharmaceutically acceptable salt thereof can be administered in combination with compound II and/or a pharmaceutically acceptable salt thereof and compound IV and/or a pharmaceutically acceptable salt thereof.

In one aspect, the disclosure features a pharmaceutical composition that includes a compound of formula (I) and/or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In one aspect, the disclosure features a pharmaceutical composition that includes a compound of formula (I) and/or a pharmaceutically acceptable salt thereof, compound II and/or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In one aspect, the disclosure features a pharmaceutical composition that includes a compound of formula (I) and/or a pharmaceutically acceptable salt thereof, compound III and/or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In one aspect, the disclosure features a pharmaceutical composition that includes a compound of formula (I) and/or a pharmaceutically acceptable salt thereof, compound II and/or a pharmaceutically acceptable salt thereof, compound III and/or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Any of the novel compounds disclosed herein, such as compounds of formula (I) and pharmaceutically acceptable salts thereof, and deuterated derivatives of such compounds and salts, can be included in a single pharmaceutical composition or in separate pharmaceutical compositions in combination with other additional active pharmaceutical ingredients (e.g., compound II, III, or IV, or a pharmaceutically acceptable salt thereof, or a deuterated derivative of such compound or salt). In some embodiments, the disclosure features a pharmaceutical composition that includes at least one compound selected from any of the compounds disclosed herein, and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier.

In some embodiments, the disclosure features a pharmaceutical composition that includes at least one compound selected from the novel compounds disclosed herein and pharmaceutically acceptable salts thereof, at least one compound selected from compound II and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier.

In some embodiments, the disclosure features a pharmaceutical composition that includes at least one compound selected from the novel compounds disclosed herein and pharmaceutically acceptable salts thereof, at least one compound selected from compound III and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier.

In some embodiments, the disclosure features a pharmaceutical composition that includes at least one compound selected from the novel compounds disclosed herein and pharmaceutically acceptable salts thereof, at least one compound selected from compound II and pharmaceutically acceptable salts thereof, at least one compound selected from compound III and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier.

In some embodiments, the disclosure features a pharmaceutical composition that includes at least one compound selected from the novel compounds disclosed herein and pharmaceutically acceptable salts thereof, at least one compound selected from compound III and pharmaceutically acceptable salts thereof, at least one compound selected from compound IV and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier.

In some embodiments, the pharmaceutical composition disclosed herein comprises at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR corrector. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR potentiator. In some embodiments, the pharmaceutical composition comprises: (i) a compound of formula (I), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C) and (VI-D), or a pharmaceutically acceptable salt thereof, or a deuterated derivative of such a compound or salt; and (ii) at least two additional active pharmaceutical ingredients, one of which is a CFTR corrector and one of which is a CFTR potentiator.

In some embodiments, the at least one additional active pharmaceutical ingredient is selected from the group consisting of mucolytics, bronchodilators, antibiotics, anti-infective agents, and anti-inflammatory agents.

The pharmaceutical composition may further comprise at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable vehicle and a pharmaceutically acceptable adjuvant. In some embodiments, the at least one pharmaceutically acceptable carrier is selected from the group consisting of pharmaceutically acceptable fillers, disintegrants, surfactants, binders, lubricants.

It is also understood that the pharmaceutical compositions of the present disclosure, including pharmaceutical compositions comprising the previously described combinations, can be used in combination therapy; that is, the composition may be administered simultaneously with, prior to, or after at least one additional active pharmaceutical ingredient or medical procedure.

Pharmaceutical compositions comprising these combinations are suitable for the treatment of cystic fibrosis.

As described above, the pharmaceutical compositions disclosed herein may optionally further comprise at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier may be selected from adjuvants and vehicles. As used herein, the at least one pharmaceutically acceptable carrier includes any and all solvents, diluents, other liquid vehicles, dispersing aids, suspending aids, surfactants, isotonic agents, thickening agents, emulsifiers, preservatives, solid binders, and lubricants suitable for the particular dosage form desired. The Science and Practice of Pharmacy, 21 st edition, 2005, D.B. Troy, eds, Lippincott Williams & Wilkins, Philadelphia and Encyclopedia of Pharmaceutical Technology, J.Swarbrick and J.C. Boylan, eds, 1988A 1999, Marcel Dekker, New York disclose various vehicles for formulating Pharmaceutical compositions and known techniques for their preparation unless any conventional carrier is incompatible with The disclosed compounds, such as by producing any undesirable biological effects or otherwise interacting in a deleterious manner with any of The other components of The Pharmaceutical composition, its use is contemplated to be within The scope of The present invention. Non-limiting examples of suitable pharmaceutically acceptable carriers include, but are not limited to: ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salts), colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polypropylene oxide-block copolymers, lanolin, sugars (such as lactose, glucose and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, ringer's solution, ethanol, phosphate buffer solution, nontoxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), colorants, releasing agents, coating agents, sweeteners, flavoring agents, fragrances, preservatives, and antioxidants.

In some embodiments, the methods of the present disclosure employ administering to a patient in need thereof at least one compound selected from any one of the compounds of formula I and pharmaceutically acceptable salts thereof, and at least one compound selected from compound II, compound III, compound IV, and pharmaceutically acceptable salts of any of the foregoing.

Any suitable pharmaceutical composition known in the art may be used for the novel compounds disclosed herein, compound II, compound III, compound IV, and pharmaceutically acceptable salts thereof. Some exemplary pharmaceutical compositions for compound II and pharmaceutically acceptable salts thereof can be found in WO 2011/119984 and WO 2014/015841, which are all incorporated herein by reference some exemplary pharmaceutical compositions for compound III and pharmaceutically acceptable salts thereof can be found in WO 2007/134279, WO 2010/019239, WO 201I/019413, WO 2012/027731 and WO 2013/130669, which are all incorporated herein by reference some exemplary compositions comprising compound III-d and pharmaceutically acceptable salts thereof can be found in, for example, WO 2014/078842 and WO2018/227049, which are incorporated herein by reference. Some exemplary pharmaceutical compositions for compound IV and pharmaceutically acceptable salts thereof can be found in WO 2010/037066, WO 2011/127241, WO 2013/112804 and WO 2014/071122, which are all incorporated herein by reference.

In some embodiments, a pharmaceutical composition comprising at least one compound selected from the novel compounds disclosed herein and pharmaceutically acceptable salts thereof is administered with a pharmaceutical composition comprising compound II and compound III. Pharmaceutical compositions comprising compound II and compound III are disclosed in PCT publication No. WO 2015/160787, which is incorporated herein by reference. Exemplary embodiments are shown in table 2 below:

table 2. exemplary tablets containing 100mg of compound II and 150mg of compound III.

In some embodiments, a compound comprising at least one member selected from the novel compounds disclosed herein and pharmaceutically acceptable salts thereof is administered with a pharmaceutical composition comprising compound III, the pharmaceutical composition comprising compound III is disclosed in PCT publication No. WO 2010/019239, which is incorporated herein by reference. Exemplary embodiments are shown in table 3 below:

table 3: ingredients of an exemplary tablet of Compound III

Additional pharmaceutical compositions comprising compound III are disclosed in PCT publication No. WO 2013/130669, which is incorporated herein by reference. Exemplary mini-tablets (approximately 2 mm in diameter, approximately 2 mm in thickness, approximately 6.9mg per mini-tablet) were formulated to have approximately 50mg of compound III per 26 mini-tablets and approximately 75mg of compound III per 39 mini-tablets using the amounts of ingredients listed in table 4 below.

Table 4: composition for 50mg and 75mg potency mini-tablets

In some embodiments, the pharmaceutical composition is a tablet. In some embodiments, the tablet is suitable for oral administration.

The compounds of the present disclosure, pharmaceutically acceptable salts thereof, and deuterated analogs of any of the foregoing, as well as pharmaceutical compositions, are useful in the treatment of cystic fibrosis, either in monotherapy or in combination therapy.

In some embodiments, disclosed herein are methods of treating, reducing the severity of, or symptomatically treating cystic fibrosis in a patient, comprising administering to a patient (such as a human) an effective amount of a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a deuterated analog of any of the foregoing, or a pharmaceutical composition, wherein the patient has cystic fibrosis.

As used herein, "Minimal Function (MF) mutation" refers to a CFTR gene mutation associated with minimal CFTR function (almost non-functional CFTR protein) and includes, for example, mutations associated with a severe lack of the ability to open and close CFTR channels, referred to as defective channel gating or "gating mutations"; mutations associated with the treatment of cells severely deficient in CFTR and their delivery to the cell surface; mutations associated with no (or minimal) CFTR synthesis; in some embodiments, if a mutation meets at least 1 of the 2 criteria below, then it is considered a MF mutation:

Biological rationality for untranslated proteins (gene sequences predicting complete absence of CFTR protein), or

In vitro tests supporting a lack of response to compound II, compound III, or a combination of compound II and compound III, as well as evidence of population-based clinical severity (as reported by large patient registries).

In some embodiments, the minimal function mutations are those that result in an almost non-functional CFTR protein and are non-responsive to compound II, compound III, or a combination of compound II and compound III in vitro.

In some embodiments, the minimal function mutations are those that are non-responsive to compound II, compound III, or a combination of compound II and compound III in vitro.

Baseline chloride ion transport of < 10% wild-type CFTR, and

chloride ion transport increased < 10% compared to baseline after addition of compound II, compound III or compound II/compound III in the assay.

In some embodiments, patients with at least one minimal functional mutation exhibit evidence of a defined clinical severity, such as:

An average sweat chloride ion of > 86mmol/L, and

incidence of Pancreatic Insufficiency (PI) is > 50%.

In some embodiments, patients with F508 del/minimal functional genotype are heterozygous F508del-CFTR patients, wherein the second CFTR allele contains a mutation that produces a CFTR protein with minimal CFTR function (a nearly non-functional CFTR protein) and is non-responsive to compound II, compound III, or a combination of compound II and compound III in vitro.

In some embodiments, the minimal functional mutation can be determined using 3 major sources:

● biological reasonableness of responsive mutations (i.e., mutation classes)

● evidence based on clinical severity of the population (patient enrollment according to CFTR 2; acquired 2 months and 15 days 2016)

Average sweat chloride ion > 86mmol/L, and

incidence of Pancreatic Insufficiency (PI) > 50%

● in vitro test

Mutations that result in baseline chloride transport < 10% of wild-type CFTR were considered minimally functional

Mutations that result in chloride transport of < 10% wild-type CFTR after addition of compound II and/or compound III are considered non-reactive.

As used herein, reference to "residual functional mutations" is a class II to V mutation that has some residual chloride ion transport and produces a less severe clinical phenotype. Residual functional mutations are mutations in the CFTR gene that result in a reduction in the amount or function of the protein at the cell surface, which may result in partial CFTR activity.

Non-limiting examples of CFTR gene mutations known to produce residual functional phenotypes include CFTR residual functional mutations selected from the group consisting of: 2789+5G → A, 3849+10kbC → T, 3272-26A → G, 711+3A → G, E56K, P67L, R74W, D110E, D1110H, R117C, L206W, R347H, R352Q, A455E, D579G, E831X, S945L, S977F, F1052V, R1070W, F1074L, D1152H, D1270N, E193K and K1060T. For example, CFTR mutations that result in defective mRNA splicing (such as 2789+507) result in reduced protein synthesis, but deliver some functional CFTR to the cell surface to provide residual function. In some embodiments, CFTR residual function mutations are selected from R117H, S1235R, I1027T, R668T, G576T, M470T, L997T, R75T, R1070T, R31T, D614T, G1069T, R1162T, E56T, a1067T, E193T, and k1060t.

Residual CFTR function can be characterized at the cellular (in vitro) level using cell-based assays to measure the amount of chloride ion transport through mutant CFTR channels, such as the FRT assay (Van Goor, f. et al (2009) PNAS vol 106, vol 44, 18825-18830; and Van Goor, f. et al (2011) PNAS vol 108, vol 46, 18843-18846). Residual functional mutations result in a reduction, but not complete elimination, of CFTR-dependent ion transport. In some embodiments, the residual functional mutation results in at least about a 10% reduction in CFTR activity in an FRT assay. In some embodiments, the residual functional mutation results in a reduction in CFTR activity in an FRT assay of up to about 90%.

Patients with F508 del/residual functional genotype are defined as heterozygous F508del-CFTR patients, where the second CFTR allele contains mutations that result in reduced protein amount or function at the cell surface, which may result in partial CFTR activity.

Patients with the F508 del/gated mutant genotype were defined as heterozygous F508del-CFTR patients, where the second CFTR allele contained a mutation associated with a gated defect and clinically confirmed to be responsive to compound III. Examples of such mutations include: G178R, S549N, S549R, G551D, G551S, G1244E, S1251N, S1255P and G1349D.

In some embodiments, the methods of treating, reducing the severity of, or symptomatically treating cystic fibrosis disclosed herein each independently prompt an increase in chloride transport above the patient's baseline chloride transport.

In some embodiments, the patient is heterozygous for F508del, and the other CFTR gene mutation is any CF pathogenic mutation, and is expected to be responsive to and/or to any of the novel compounds disclosed herein (such as the compound of formula (I)), compound II, compound III and/or compound IV genotypes based on in vitro and/or clinical data And/or compound III and/or compound IV genotypes.

In some embodiments, in the methods of treating, reducing the severity of, or symptomatically treating cystic fibrosis disclosed herein, the patient has a mutation in the CFTR gene selected from any one of the mutations listed in table a.

Table a. cf mutations

In some embodiments, in the methods of treating, reducing the severity of, or symptomatically treating cystic fibrosis disclosed herein, the patient has a CFTR gene mutation selected from: G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110C, R347C, R352C, E56C, P67C, L206C, A455C, D579C, S1235C, S945C, R1070C, F1074C, D110C, D127360, D1152 + G > C, 1717-1G- > A, 621+1G- > T, 3120+1G- > A, 1898+1G- > A, 711+1G- > T, 406 2+1G- > A, 405+1G- > A, G- > 5A-1245G- > 1A, G- > 1A-42-1G- > A, 433649, G- > 1A- > 1A, 43388, 3-G- > A, 433672, 3-G- > A- > G- > 1A, 43381A- > 1, 3-G- > A, 3-G- > A- > G, 3272-26A- > G, 711+5G- > A, 3120G- > A, 1811+ 1.6- > G, 711+3A- > G, 1898+3A- > G, 1717-8G- > A, 1342-2A- > C, 405+3A- > C, 1716G/A, 1811+1G- > C, 1898+5G- > T, 3850-3T- > 14 +5G- > A, 1898+1G- > T, 4005+2T- > C, 621+3A- > G, 1949del, 3141del, 3195del, 3199del, 3905InsT, 4209TGTT- > 120, A234, A349, A613, C524, D192, D443, D979, E116, E403, E575, E822, E54, F311, F31, F311, F31, F311, F, G126, G149, G194, G27, G314, G458, G463, G480, G622, G628 (G- > A), G91, G970, H1054, H1085, H1375, H139, H199, H609, H939, I1005, I1234, I1269, I1366, I175, I502, I506, I601, I618, I807, I980, L102, L1324, L1335, L138ins, L1480, L15, L165, L320, L346, L453, L553, L967, M1101, M152, M1, M952, M574, P5, P750, P99, Q562, Q1291, Q237, Q452, Q98, R6, R1246, R1247, M952, P1240, R2, R102, R1240, S359, S102, S359, S2049, R2, S20411, R2, R20411, R3, S20411, R2R 3, R3R 102, S20411, S3, S2R 3R 2R 3R 2R 3R 2R 102, S2R 3R 2R 3R, Y1032C, Y109N, Y161D, Y161S, Y563D, Y563N, Y569C, and Y913C.

In some embodiments, the patient has at least one combinatorial mutation selected from: G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110C, R347C, R352C, E56C, P67C, L206C, A455C, D579C, S1235C, S945C, R1070C, F1074C, D110C, D127360, D1152 + G > C, 1717-1G- > A, 621+1G- > T, 3120+1G- > A, 1898+1G- > A, 711+1G- > T, 406 2+1G- > A, 405+1G- > A, G- > 5A-1245G- > 1A, G- > 1A-42-1G- > A, 433649, G- > 1A- > 1A, 43388, 3-G- > A, 433672, 3-G- > A- > G- > 1A, 43381A- > 1, 3-G- > A, 3-G- > A- > G, 3272-26A- > G, 711+5G- > A, 3120G- > A, 1811+1.6kbA- > G, 711+3A- > G, 1898+3A- > G, 1717-8G- > A, 1342-2A- > C, 405+3A- > C, 1716G/A, 1811+1G- > C, 1898+5G- > T, 3850-3T- > G, IVS14b +5G- > A, 1898+1G- > T, 4005+2T- > C and 621+3A- > G.

In some embodiments, the patient has at least one combinatorial mutation selected from: 1949del, 3141del, 3195del, 3199del, 3905InsT, 4209TGTT- > 1006, A120, A234, A349, A613, C524, D192, D443, D513, D836, D924, D979, E116, E403, E474, E588, E60, E822, F1016, F1099, F191, F311del, F311, F508, F575, G1061, G1249, G126, G149, G194, G346, G314, G458, G463, G480, G622, G628 (G- > A), G91, G970, H1054, H1085, H1375, H139, H199, H609, H939, I1005, I1234, I9, I1366, I506, I502, I618, I1085, L1375, R1375, H139, L9611, L967, R102, L9611, R102, L967, R20411, L967, R102, L9611, R20411, L3, R2043, L3, R20411, R11, L16, R20411, R11, R20411, L3, R11, L16, R20411, R11, L16, R1, L3, R11, R20411, R1, R11, L967, R11, L3, R11, R20411, R751L, R792G, R933G, S1118F, S1159F, S1159P, S13F, S549R (a- > C), S549R (T- > G), S589N, S737F, S912L, T1036N, T1053I, T1246I, T604I, V1153E, V1240G, V1293G, V201M, V232D, V456A, V562A, W1098A, W1282A, W361A, W57A, Y1014A, Y1032A, Y109A, Y161 36563, Y A, Y36563 365639, Y365639 and Y36913.

In some embodiments, in the methods of treating, reducing the severity of, or symptomatically treating cystic fibrosis disclosed herein, the patient has the CFTR gene mutation, G551d. In some embodiments, the patient is heterozygous for a G551D gene mutation, has a G551D mutation on one allele and has any other CF disease causing mutation on the other allele. F508del, G542X, N1303K, W1282X, R117H, R553X, 1717-1G- > a, 621+1G- > T, 2789+5G- > a, 3849+10kbC- > T, R1162X, G85E, 3120+1G- > a, Δ I507, 1898+1G- > a, 3659delC, R347P, R560T, R334W, a455E, 2184delA, or 711+1G- > T.

In some embodiments, in the methods of treating, reducing the severity of, or symptomatically treating cystic fibrosis disclosed herein, the patient has the CFTR gene mutation F508 del. In some embodiments, the patient is heterozygous for the F508del gene mutation, wherein the patient has the F508del gene mutation on one allele and any CF disease causing gene mutations on the other allele. In some embodiments, the patient is heterozygous for F508del, and the other CFTR gene mutation is any CF-causing mutation, including but not limited to: G551D, G542X, N1303K, W1282X, R117H, R553X, 1717-1G- > A, 621+1G- > T, 2789+5G- > A, 3849+10kbC- > T, R1162X, G85E, 3120+1G- > A, Δ I507, 1898+1G- > A, 3659delC, R347P, R560T, R334W, A455E, 2184delA or 711+1G- > T. In some embodiments, the patient is heterozygous for F508del and the other CFTR gene mutation is g551d in some embodiments, the patient is heterozygous for F508del and the other CFTR gene mutation is R117H.

In some embodiments, the patient has at least one combinatorial mutation selected from:

D443Y；G576A；R668C，

F508C；S1251N，

G576A；R668C，

G970R；M470V，

R74W；D1270N，

R74W; V201M, and

R74W；V201M；D1270N.

in some embodiments, in the methods of treating, reducing the severity of, or symptomatically treating cystic fibrosis disclosed herein, the patient has a CFTR gene mutation selected from: G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V and G1069r in some embodiments, the patient has a mutation in the CFTR gene selected from: G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R and S1251N. In some embodiments, the patient has a CFTR gene mutation selected from the group consisting of E193K, F1052V, and G1069R in some embodiments, the method promotes an increase in chloride transport relative to the patient's baseline chloride transport.

In some embodiments, in the methods of treating, reducing the severity of, or symptomatically treating cystic fibrosis disclosed herein, the patient has a CFTR gene mutation selected from: R117C, D110H, R347H, R352Q, E56K, P67L, L206W, a455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N and D1152H.

In some embodiments, the patient has a CFTR gene mutation selected from: 1717-1G- > A, 621+1G- > T, 3120+1G- > A, 1898+1G- > A, 711+1G- > T, 2622+1G- > A, 405+1G- > A, 406-1G- > A, 4005+1G- > A, 1812-1G- > A, 1525-1G- > A, 712-1G- > T, 1248+1G- > A, 1341+1G- > A, 3121-1G- > A, 4374+1G- > T, 3850-1G- > A, 2789+5G- > A, 3849+10kbC- > T, 3272-26A- > G, 711+5G- > A, 3120G- > A, 1811+1.6kbA- > G, 711+3A- > G, 1898+3A- > G, 1717-8G- > A, 1342-2A- > C, 405+3A- > C, 1716G/A, 1811+1G- > C, 1898+5G- > T, 3850-3T- > G, IVS14b +5G- > A, 1898+1G- > T, 4005+2T- > C and 621+3A- > G. In some embodiments, the patient has a CFTR gene mutation selected from: 1717-1G- > A, 1811+1.6kbA- > G, 2789+5G- > A, 3272-26A- > G, and 3849+10kbC- > T in some embodiments, the patient has a mutation in the CFTR gene selected from 2789+5G- > A and 3272-26A- > G.

In some embodiments, in the methods of treating, reducing the severity of, or symptomatically treating cystic fibrosis disclosed herein, the patient has a CFTR gene mutation selected from: G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110C, R347C, R352C, E56C, P67C, L206C, A455C, D579C, S1235C, S945C, R1070C, F1074C, D110C, D127360, D1152 + G > C, 1717-1G- > A, 621+1G- > T, 3120+1G- > A, 1898+1G- > A, 711+1G- > T, 406 2+1G- > A, 405+1G- > A, G- > 5A-1245G- > 1A, G- > 1A-42-1G- > A, 433649, G- > 1A- > 1A, 43388, 3-G- > A, 433672, 3-G- > A- > G- > 1A, 43381A- > 1, 3-G- > A, 3-G- > A- > G, 3272-26A- > G, 711+5G- > A, 3120G- > A, 1811+1.6kbA- > G, 711+3A- > G, 1898+3A- > G, 1717-8G- > A, 1342-2A- > C, 405+3A- > C, 1716G/A, 1811+1G- > C, 1898+5G- > T, 3850-3T- > G, IVS14b +5G- > A, 1898+1G- > T, 4005+2T- > C and 621+3A- > G, and human CFTR mutations selected from F508del, R117H and G551D.

In some embodiments, in the methods of treating, reducing the severity of, or symptomatically treating cystic fibrosis disclosed herein, the patient has a CFTR gene mutation selected from: G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110C, R347C, R352C, E56C, P67C, L206C, A455C, D579C, S1235C, S945C, R1070C, F1074C, D110C, D127360, D1152 + G > C, 1717-1G- > A, 621+1G- > T, 3120+1G- > A, 1898+1G- > A, 711+1G- > T, 406 2+1G- > A, 405+1G- > A, G- > 5A-1245G- > 1A, G- > 1A-42-1G- > A, 433649, G- > 1A- > 1A, 43388, 3-G- > A, 433672, 3-G- > A- > G- > 1A, 43381A- > 1, 3-G- > A, 3-G- > A- > G, 3272-26A- > G, 711+5G- > A, 3120G- > A, 1811+1.6kbA- > G, 711+3A- > G, 1898+3A- > G, 1717-8G- > A, 1342-2A- > C, 405+3A- > C, 1716G/A, 1811+1G- > C, 1898+5G- > T, 3850-3T- > G, IVS14b +5G- > A, 1898+1G- > T, 4005+2T- > C, 621+3A- > G, and a CFTR mutation selected from F508del, R117H, and G551D; and a CFTR mutation selected from F508del, R117H, and G551D.

In some embodiments, the patient has a CFTR gene mutation selected from: G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V and G1069R, and human CFTR mutations selected from F508del, R117H and G551D. In some embodiments, the patient has a CFTR gene mutation selected from: G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R and S1251N, and a human CFTR mutation selected from F508del, R117H and G551D in some embodiments, the patient has a CFTR gene mutation selected from E193K, F1052V and G1069R, and a human CFTR mutation selected from F508del, R117H and G551D.

In some embodiments, the patient has a CFTR gene mutation selected from: R117C, D110H, R347H, R352Q, E56K, P67L, L206W, a455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N and D1152H, and a human CFTR mutation selected from F508del, R117H and G551D.

In some embodiments, the patient has a CFTR gene mutation selected from: 1717-1G- > A, 621+1G- > T, 3120+1G- > A, 1898+1G- > A, 711+1G- > T, 2622+1G- > A, 405+1G- > A, 406-1G- > A, 4005+1G- > A, 1812-1G- > A, 1525-1G- > A, 712-1G- > T, 1248+1G- > A, 1341+1G- > A, 3121-1G- > A, 4374+1G- > T, 3850-1G- > A, 2789+5G- > A, 3849+10kbC- > T, 3272-26A- > G, 711+5G- > A, 3120G- > A, 1811+1.6kbA- > G, 711+3A- > G, 1898+3A- > G, 1717-8G- > A, 1342-2A- > C, 405+3A- > C, 1716G/A, 1811+1G- > C, 1898+5G- > T, 3850-3T- > G, IVS14 + 14b +5G- > A, 1898+1G- > T, 4005+2T- > C and 621+3A- > G, and a human CFTR mutation selected from F508del, R117H and G551D. 1717-1G- > A, 1811+1.6kbA- > G, 2789+5G- > A, 3272-26A- > G and 3849+10kbC- > T, and a human CFTR mutation selected from F508del, R117H and G551D. In some embodiments, the patient has a CFTR gene mutation selected from 2789+5G- > A and 3272-26A- > G and a human CFTR mutation selected from F508del, R117H.

In some embodiments, the patient is heterozygous for F508del, and the other CFTR gene mutation is any CF pathogenic mutation, including but not limited to: in some embodiments, the CF-causing mutation is selected from table a. in some embodiments, the CF-causing mutation is selected from table b. in some embodiments, the CF-causing mutation is selected from table c. in some embodiments, the CF-causing mutation is selected from figure 2. In some embodiments, the patient is heterozygous having a CF-causing mutation on one CFTR allele selected from the mutations listed in the table from figure 2, and a CF-causing mutation on the other CFTR allele selected from the CFTR mutations listed in table B:

table B: CFTR mutation

Table C: CFTR mutation

Note that: % PI: percentage of F508del-CFTR heterozygous patients in CFTR2 patient enrollment for pancreatic insufficiency; SwCl^-: mean sweat chloride of F508deI-CFTR heterozygous patients enrolled in CFTR2 patients

^aAlso known as 2183delAA → G.

^bNo data is published.

In some embodiments, the patient is: has the F508deI/MF (F/MF) genotype (F508del is heterozygous and the MF mutation is expected to be unresponsive to CFTR modulators, such as Compound III); has a genotype of F508del/F508del (F/F) (homozygous for F508 del); and/or has an F508 del/gating (F/G) genotype (F508del is heterozygous and the gating mutation is known to be CFTR modulator reactive (e.g., compound III reactive) — in some embodiments, patients having an F508del/MF (F/MF) genotype have MF mutations that are expected to be non-responsive to compound II, compound III, and both compound II and compound III.

In some embodiments, the patient is heterozygous for F508del, and the other CFTR gene mutation is any CF-pathogenic mutation, including truncation mutations, splicing mutations, small (< 3 nucleotides) insertion or deletion (ins/del) frame shift mutations, non-small (> 3 nucleotides) insertion or deletion (ins/del) frame shift mutations, and class II, class III, class IV mutations that are non-reactive to compound III, alone or in combination with compound II or compound IV.

In some embodiments, the patient is heterozygous for F508del, and the other CFTR gene mutation is a truncation mutation. In some embodiments, the truncation mutations are those listed in table C.

In some embodiments, the patient is heterozygous for F508del, and the other CFTR gene mutation is a splicing mutation. In some embodiments, the splice mutation is a splice mutation listed in table C.

In some embodiments, the patient is heterozygous for F508del, and the other CFTR gene mutation is a small (< 3 nucleotides) insertion or deletion (ins/del) frameshift mutation in some embodiments, the small (< 3 nucleotides) insertion or deletion (ins/del) frameshift mutation is a small (< 3 nucleotides) insertion or deletion (ins/del) frameshift mutation listed in Table C.

In some embodiments of the compounds of formulae (I), (II-a), (II-B), (III-a), (III-B), (IV-a), (IV-B), (IV-C), (V-a), (V-B), (VI-a), (VI-B), (VI-C), and (VI-D), as well as pharmaceutically acceptable salts thereof, and deuterated derivatives thereof, the patient is F508del heterozygous and the other CFTR gene mutation is any CF causative mutation expected to be responsive to and/or any combination of the following based on in vitro and/or clinical data: (i) novel compounds selected from those disclosed herein (e.g., compounds of formulae (I), (II-a), (II-B), (III-a), (III-B), (IV-a), (IV-B), (IV-C), (V-a), (V-B), (VI-a), (VI-B), (VI-C), and (VI-D), and pharmaceutically acceptable salts thereof, and deuterated derivatives thereof), and (II) compound II, and/or compound III, and/or compound IV.

In some embodiments, the patient is F508del heterozygous and the other CFTR gene mutation is any CF pathogenic mutation expected to respond to and/or to a novel compound selected from those disclosed herein (e.g., derivatives) in triple combinations of compound II and compound III based on in vitro and/or clinical data.

In some embodiments, the patient is heterozygous for F508del, and the other CFTR gene mutation is a non-small (> 3 nucleotides) insertion or deletion (ins/del) frameshift mutation. In some embodiments, the non-small (> 3 nucleotide) insertion or deletion (ins/del) frame shift mutations are the non-small (> 3 nucleotide) insertion or deletion (ins/del) frame shift mutations listed in table C.

In some embodiments, the class II, III, IV mutations that are non-responsive to compound III, either alone or in combination with compound II or compound IV are the class II, III, IV mutations listed in table C that are non-responsive to compound III, either alone or in combination with compound II or compound IV.

In some embodiments, the patient is heterozygous for F508del, and the other CFTR gene mutation is any of the mutations listed in table C.

In some embodiments, the patient is heterozygous for F508del, and the other CFTR gene mutation is any mutation listed in table a, table B, table C, and figure 2 other than F508 del.

In some embodiments, the patient is heterozygous for F508del, and the other CFTR gene mutation is any of the mutations listed in table a. In some embodiments, the patient is heterozygous for F508del, and the other CFTR gene mutation is any of the mutations listed in table B. In some embodiments, the patient is heterozygous for F508del, and the other CFTR gene mutation is any of the mutations listed in table C. In some embodiments, the patient is heterozygous for F508del, and the other CFTR gene mutation is any of the mutations listed in figure 2.

In some embodiments, the patient is homozygous for F508 del.

In some embodiments, the patient is heterozygous having a CF-causing mutation on one CFTR allele selected from the mutations listed in the table from figure 2, and another CF-causing mutation on another CFTR allele selected from the CFTR mutations listed in table C.

In some embodiments, the compositions disclosed herein are suitable for treating, reducing the severity of, or symptomatically treating cystic fibrosis in a patient exhibiting residual CFTR activity in the apical membrane of respiratory and non-respiratory epithelia. Such methods use in vivo or ex vivo electrophysiological techniques, sweat or saliva Cl^-Measurement of concentration or monitoring of cell surface density using ex vivo biochemical or histochemical techniques to identify CFTR activity. In some embodiments, the compositions disclosed herein are useful for treating, reducing the severity of, or symptomatically treating cystic fibrosis in a patient who exhibits little residual CFTR activity in the apical membrane of the respiratory epithelium.

In some embodiments, the compositions disclosed herein are suitable for treating or reducing the severity of cystic fibrosis in a patient exhibiting residual CFTR activity using pharmacological methods. Such methods increase the amount of CFTR present on the cell surface, thereby inducing CFTR activity that is not present to date in the patient or potentiating existing levels of residual CFTR activity in the patient.

In some embodiments, the compositions disclosed herein are suitable for treating or reducing the severity of cystic fibrosis in a patient having certain genotypes exhibiting residual CFTR activity.

In some embodiments, the compositions disclosed herein are suitable for treating, reducing the severity of, or symptomatically treating cystic fibrosis in a patient having certain clinical phenotypes, such as a mild to moderate clinical phenotype typically associated with the amount of residual CFTR activity in the epithelial apical membrane.

In some embodiments, the compositions disclosed herein are suitable for treating, reducing the severity of, or treating symptoms of a patient diagnosed with pancreatic insufficiency, idiopathic pancreatitis, and congenital bilateral vasectomy deficient or mild lung disease, wherein the patient exhibits residual CFTR activity.

In some embodiments, the present disclosure relates to a method of potentiating or inducing anion channel activity in vitro or in vivo comprising contacting a channel with a composition disclosed herein. In some embodiments, the anion channel is a chloride channel or a bicarbonate channel.

In some embodiments, the patient is heterozygous and has an F508del mutation on one allele and a mutation selected from table 5 on the other allele:

table 5: CFTR mutation

The precise amount of a desired pharmaceutical composition will vary from subject to subject depending on the species, age, and general condition of the subject, the severity of the disease, the particular agent, its mode of administration, and the like. The activity of the particular compound employed; the specific composition used; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the particular compound employed; the duration of treatment; medicaments for use in combination or concomitantly with the specific compounds employed; as used herein, the term "patient" refers to an animal, such as a mammal and further such as a human.

In some embodiments, compound III-d as used herein includes deuterated compounds disclosed in U.S. patent No. 8,865,902 (which is incorporated herein by reference), such as:

clinical efficacy of compound III-d in combination with other CFTR correctors (including in combination with compound II) has been described in Davies et al New engl.j.med.379 (17): 1599 + 1611(2018) and Davies et al New Engl. J. Med.379 (17): 1612-1620 (2018).

Exemplary embodiments of the present disclosure include: the novel compounds disclosed herein (e.g., compounds of formulae (I), (II-a), (II-B), (III-a), (III-B), (IV-a), (IV-B), (IV-C), (V-a), (V-B), (VI-a), (VI-B), (VI-C), and (VI-D), pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing, including the compounds in fig. 1 and those specifically delineated herein) can be prepared by suitable methods known in the art. For example, the novel compounds of formula (I), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C) and (VI-D), and deuterated derivatives of pharmaceutically acceptable salts thereof, can be combined with the compounds for use in the compositions of formula (I), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B) The compounds of (VI-C) and (VI-D), and pharmaceutically acceptable salts thereof, are prepared in a manner similar to that described above by employing intermediates and/or reagents wherein one or more hydrogen atoms is replaced by deuterium. See, for example, t.g.gate "Using the material in drug discovery: leaving the label in the drug, "j.med.chem.2014, 57, 3595-.

In some embodiments, the compounds disclosed herein and pharmaceutically acceptable salts thereof, as well as deuterated derivatives of any of the foregoing, are prepared as depicted in schemes 1 through 12, wherein the variables are each and independently the same as those of formula (I). The methods disclosed herein can be used to prepare compounds of formula (I), (II-A), (II-B), (III-A), (III-B), (IV-A), (IV-B), (IV-C), (V-A), (V-B), (VI-A), (VI-B), (VI-C), and (VI-D) as well as any of the compounds depicted in Table 5 and FIG. 1, a salt thereof, or a deuterated derivative of any of the foregoing.

In some embodiments, as shown in scheme 1, the method comprises reacting a compound of formula (a) or a salt thereof with a compound of formula (B) or a salt thereof to produce a compound of formula (Y), a salt thereof, or a deuterated derivative of any of the foregoing. The reactions of formula (a) and formula (B) may be carried out under any suitable coupling reaction between a carboxylic acid and a sulfonamide, such as with CDI. In some embodiments, the coupling reaction is carried out in the presence of a base (such as DBU).

Scheme 1

In some embodiments, as shown in scheme 2, the method comprises deprotecting a compound of formula (Y) to produce a compound of formula (Y-1), a salt thereof, or a deuterated derivative of any of the foregoing The protection may be carried out under any suitable deprotection conditions, depending on the protecting group R¹⁰As will be apparent to those skilled in the art. In some embodiments, the protecting group R¹⁰Boc, and the deprotection conditions are acidic. In some embodiments, as shown in scheme 2, the method comprises reacting a compound of formula (Y-1) to produce a compound of formula (I), a salt thereof, or a deuterated derivative of any of the foregoing the reaction of formula (Y-1) can be carried out under any suitable coupling reaction between an amine and a halogen. In some embodiments, the coupling reaction is in a base (such as K)₂CO₃) In the presence of oxygen.

Scheme 2

In some embodiments, as shown in scheme 3, the method comprises reacting a compound of formula (a) or a salt thereof with a compound of formula (B-2) or a salt thereof to produce a compound of formula (Y-2), a salt thereof, or a deuterated derivative of any of the foregoing.

Scheme 3

In some embodiments, as shown in scheme 4, the method comprises reacting a compound of formula (D) or a salt thereof with a compound of formula (E-2) or a salt thereof to produce a compound of formula (B-2), a salt thereof, or a deuterated derivative of any of the foregoing. The reaction of formula (D) with formula (E-2) can be carried out under any suitable coupling reaction between the amine and Rd.

Scheme 4

In some embodiments, as shown in scheme 5, the method comprises reacting a compound of formula (a) or a salt thereof with a compound of formula (B-3) or a salt thereof to produce a compound of formula (Y-3), a salt thereof, or a deuterated derivative of any of the foregoing.

Scheme 5

In some embodiments, as shown in scheme 6, the method comprises reacting a compound of formula (D) or a salt thereof with a compound of formula (E-3) or a salt thereof to produce a compound of formula (B-3), a salt thereof, or a deuterated derivative of any of the foregoing^dUnder any suitable coupling reaction.

Scheme 6

In some embodiments, as shown in scheme 7, the method comprises reacting a compound of formula (Z-1) with a compound of formula (X) to produce a compound of formula (I), a salt thereof, or a deuterated derivative of any one of the foregoing. The reaction of the compound of formula (Z-1) with the compound of formula (X) may be carried out under any suitable coupling reaction between nitrogen and halogen.

Scheme 7

In some embodiments, as shown in scheme 8, the method comprises reacting a compound of formula (Z-1) with a compound of formula (X-1) to produce a compound of formula (IV-C), a salt thereof, or a deuterated derivative of any of the foregoing. The reaction of the compound of formula (Z-1) with the compound of formula (X-1) may be carried out under any suitable coupling reaction between nitrogen and halogen.

Scheme 8

In some embodiments, as shown in scheme 9, the method comprises reacting a compound of formula (F) or a salt thereof with a compound of formula (G) or a salt thereof to produce a compound of formula (H), a salt thereof, or a deuterated derivative of any of the foregoing. The reaction of formula (F) with formula (G) may be carried out under any suitable reaction between the amide and the sulphur atom, such as with bromine. In some embodiments, the reaction is carried out in the presence of a base, such as pyridine. In some embodiments, the oxidizing agent is m-chloroperoxybenzoic acid (m-CPBA).

Scheme 9

In some embodiments, as shown in scheme 10, the method comprises reacting a compound of formula (J) with a compound of formula (L) to produce a compound of formula (M), a salt thereof, or a deuterated derivative of any one of the foregoing. In some embodiments, the reaction is carried out in the presence of a base (such as sodium hydride).

Scheme 10

In some embodiments, as shown in scheme 11, the method comprises reacting a compound of formula (M) or a salt thereof with an amine to produce a compound of formula (N), a salt thereof, or a deuterated derivative of any of the foregoing, wherein X is NH or N (C)₁-C₄Alkyl), in some embodiments, the reaction of formula (M) and amine may be carried out in the presence of N-chlorosuccinimide. The compound of formula (N) may be converted to a compound of formula (O), a salt thereof, or a deuterated derivative of any of the foregoing The reaction is carried out under reducing conditions. In some embodiments, the reaction is carried out in the presence of palladium on carbon and hydrogen.

Scheme 11

In some embodiments, as shown in scheme 12, the method comprises reacting a compound of formula (O) or a salt thereof to produce a compound of formula (P), a salt thereof, or a deuterated derivative of any of the foregoing. In some embodiments, the base is triethylamine. In some embodiments, the reaction of formula (O) may be carried out with heating.

Scheme 12

Additional embodiments include:

1. a compound of formula I:

wherein:

-ring B is a pyridyl ring;

-X is O, NH or N (C1-C4 alkyl);

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

-k is 0, 1, 2, 3, 4, 5 or 6;

-R⁷Selected from hydrogen, halogen, cyano and optionally substituted by one or moreC substituted by radicals from₃-C₁₀Cycloalkyl groups: c₁-C₂Alkyl radical, C₁-C₂Haloalkyl and halogen;

-q is 1, 2, 3 or 4; and is

-Z is of formula (L)_rThe divalent linker of (1), wherein:

-r is 1, 2, 3, 4, 5 or 6;

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

2. The compound of embodiment 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring a is a phenyl ring, a pyridinyl ring, or a pyrazolyl ring, wherein ring a is optionally substituted with (R)¹)_mAnd (4) substitution.

3. The compound of

embodiment

1 or 2, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is¹Independently selected from deuterium, C₁-C₂Alkyl and hydroxy, and m is 0 or 1.

4. A compound according to any one of embodiments 1 to 3, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein n is 0.

5. The compound of any one of embodiments 1 to 4, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring D is substituted with (R)⁴)_qA substituted 5-membered heteroaryl ring.

6. The compound of any one of embodiments 1 to 4, pharmaceutically acceptable salts thereof, or deuterated derivatives of any of the foregoing, wherein ring D is a phenyl ring, a pyridinyl ring, a pyrazolyl ring, an imidazolidinone ring A pyrrolidone ring or a pyridone ring wherein ring D is (R)⁴)_qAnd (4) substitution.

7. The compound of any one of embodiments 1 to 4, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring D is

Wherein

Indicating the point of attachment of ring D to ring B.

8. The compound of embodiment 7, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring D is

Wherein

Indicating the point of attachment of ring D to ring B.

9. A compound according to any one of embodiments 1 to 8, pharmaceutically acceptable salts thereof, or deuterated derivatives of any of the foregoing, wherein each R is⁴Independently selected from oxo or- (Y)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

-each Y is independently selected from C (R)⁵)(R⁶) The radicals, -O-and-NR^a-group in which- (Y)_k-R⁷Wherein the heteroatom is not bound to- (Y)_k-R⁷And wherein:

each R⁵And R⁶Independently selected from hydrogen, deuterium, halogen, hydroxy, C₁-C₄Alkyl and C_3-5Cycloalkyl radicals, or R on the same carbon⁵And R⁶Together form C_3-5Cycloalkyl or oxo;

-R⁷Selected from hydrogen, halogen, cyano and C optionally substituted by one or more groups selected from₃-C₁₀Cycloalkyl groups: c₁-C₂Alkyl radical, C₁-C₂Haloalkyl, and halogen.

10. A compound according to any one of embodiments 1 to 9, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁴Independently selected from oxo or- (Y)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

each R⁵And R⁶Independently selected from hydrogen, deuterium, halogen, hydroxy, C₁-C₄Alkyl and C_3-5Cycloalkyl radicals, or R on the same carbon⁵And R⁶Together form C_3-5A cycloalkyl group;

-R⁷Selected from hydrogen, halogen, cyanogenAnd C optionally substituted by one or more groups selected from₃-C₁₀Cycloalkyl groups: c₁-C₂Alkyl radical, C₁-C₂Haloalkyl, and halogen.

11. A compound according to any one of embodiments 1 to 8, pharmaceutically acceptable salts thereof, or deuterated derivatives of any of the foregoing, wherein each R is ⁴Independently selected from oxo or-O- (Y)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4 or 5;

12. A compound according to any one of embodiments 1 to 8, pharmaceutically acceptable salts thereof, or deuterated derivatives of any of the foregoing, wherein each R is⁴Independently selected from:

wherein

Indication R⁴The point of attachment to loop D.

13. The compound of any one of embodiments 1 to 12, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein k is 3, 4, 5, or 6.

14. A compound according to any one of embodiments 1 to 13, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein q is 1.

15. A compound according to any one of embodiments 1 to 14, pharmaceutically acceptable salts thereof, or deuterated derivatives of any of the foregoing, wherein Z is formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

-each L is independently selected from C (R)⁸)(R⁹) The radicals, -O-and-NR^b-a group wherein a heteroatom in Z is not bound to another heteroatom in Z, and wherein:

each R⁸And R⁹Independently selected from hydrogen and deuterium; and is

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

16. The compound of any one of embodiments 1 to 14, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein Z is formula (a)L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

-each L is independently selected from C (R)⁸)(R⁹) Group and-NR^b-a group wherein the heteroatom in Z is not bound to another heteroatom in Z, and:

each R⁸And R⁹Independently selected from hydrogen and deuterium; and is

Each R^bIndependently selected from hydrogen and methyl.

17. A compound according to any one of embodiments 1 to 14, pharmaceutically acceptable salts thereof, or deuterated derivatives of any of the foregoing, wherein Z is formula (L) _rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

-each L is independently selected from C (R)⁸)(R⁹) Group and-NR^b-a group wherein a heteroatom in Z is not bound to another heteroatom in Z, and wherein:

each R⁸And R⁹Independently selected from hydrogen and deuterium; and is

Each R^bIs hydrogen.

18. A compound according to any one of embodiments 1 to 14, pharmaceutically acceptable salts thereof, or deuterated derivatives of any of the foregoing, wherein Z is formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Is hydrogen; and is

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

19. A compound according to any one of embodiments 1 to 18, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is³Independently of CD₃.

20. The compound of embodiment 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein the compound of formula (I) is a compound of formula (II-a) or (II-B):

wherein:

-the carbon represented by has S-stereochemistry or R-stereochemistry;

-ring B is a pyridyl ring;

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

each R⁴Independently selected from the group consisting of halogen, hydroxy, oxo, cyano and- (Y)_k-R⁷A group, or optionally, two R⁴Together with the atoms to which they are attached form a 5-to 6-membered cycloalkyl or heterocyclyl ring optionally and independently substituted with one or more groups selected from: halogen, C₁-C₂Alkyl, haloalkyl, hydroxy, C₁-C₂Alkoxy and C₁-C₂Haloalkoxy, wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

each R⁵And R⁶Independently selected from hydrogen, halogen, hydroxy, C₁-C₄Alkyl and C_3-5Cycloalkyl radicals, or R on the same carbon ⁵And R⁶Together form C_3-5Cycloalkyl or oxo;

-q is 1, 2, 3 or 4;

-Z is of formula (L)_rThe divalent linker of (1), wherein:

-r is 1, 2, 3, 4, 5 or 6;

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

21. Trueness ofThe compound of embodiment 20, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring a is a phenyl ring, a pyridinyl ring, or a pyrazolyl ring, wherein ring a is optionally substituted with (R)¹)_mAnd (4) substitution.

22. The compound of embodiment 20 or 21, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is ¹Independently selected from deuterium, C₁-C₂Alkyl and hydroxy, and m is 0 or 1.

23. The compound of any one of embodiments 20 to 22, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein n is 0.

24. The compound of any one of embodiments 20 to 23, pharmaceutically acceptable salts thereof, or deuterated derivatives of any of the foregoing, wherein ring D is substituted with (R)⁴)_qA substituted 5-membered heteroaryl ring.

25. The compound of any one of embodiments 20 to 23, pharmaceutically acceptable salts thereof, or deuterated derivatives of any of the foregoing, wherein ring D is a pyrazolyl ring or a pyridone ring, wherein ring D is substituted with R⁴And (4) substitution.

26. A compound according to any one of embodiments 20 to 23, pharmaceutically acceptable salt thereof, or deuterated derivative of any one of the foregoing, wherein ring D is

Wherein

Indicating the point of attachment of ring D to ring B.

27. A compound according to any one of embodiments 20 to 23, pharmaceutically acceptable salt thereof, or deuterated derivative of any one of the foregoing, wherein ring D is

Wherein

Indicating the point of attachment of ring D to ring B.

28. A compound according to any one of embodiments 20 to 27, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁴Independently selected from oxo or- (Y) _k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

29. The compound of any one of embodiments 20 to 28, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein eachR⁴Independently selected from oxo or- (Y)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

each R ⁵And R⁶Independently selected from hydrogen, deuterium, halogen, hydroxy, C₁-C₄Alkyl and C_3-5Cycloalkyl radicals, or R on the same carbon⁵And R⁶Together form C_3-5A cycloalkyl group;

30. The compound of any one of embodiments 20 to 28, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁴Independently selected from oxo or-O- (Y)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4 or 5;

each R⁵And R⁶Independently selected from hydrogen, deuterium, halogenHydroxy, C₁-C₄Alkyl and C_3-5Cycloalkyl radicals, or R on the same carbon⁵And R⁶Together form C_3-5Cycloalkyl or oxo;

31. The compound of any one of embodiments 20 to 28, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁴Independently selected from:

wherein

Indication R⁴The point of attachment to loop D.

32. The compound of any one of embodiments 20 to 31, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein k is 3, 4, 5, or 6.

33. The compound of any one of embodiments 20 to 32, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein q is 1.

34. A compound according to any one of embodiments 20 to 33, pharmaceutically acceptable salts thereof, or deuterated derivatives of any of the foregoing, wherein Z is formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

Each R⁸And R⁹Independently selected from hydrogen and deuterium; and is

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

35. A compound according to any one of embodiments 20 to 33, pharmaceutically acceptable salts thereof, or deuterated derivatives of any of the foregoing, wherein Z is formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

-each L is independently selected from C (R)⁸)(R⁹) Group and-NR^b-a group wherein the heteroatom in Z is not bound to another heteroatom in Z, wherein:

each R⁸And R⁹Independently selected from hydrogen and deuterium; and is

Each R^bIndependently selected from hydrogen and methyl.

36. A compound according to any one of embodiments 20 to 33, pharmaceutically acceptable salts thereof, or deuterated derivatives of any of the foregoing, wherein Z is formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Independently selected from hydrogen and deuterium; and is

Each R^bIs hydrogen.

37. A compound according to any one of embodiments 20 to 33, pharmaceutically acceptable salts thereof, or deuterated derivatives of any of the foregoing, wherein Z is formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

-each L is independently selected from C (R)⁸)(R⁹) The radicals, -O-and-NR ^b-a group wherein the heteroatom in Z is not bound to another heteroatom in Z, wherein:

each R⁸And R⁹Is hydrogen; and is

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

38. A compound according to any one of embodiments 20 to 37, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is³Independently of CD₃。

39. The compound of embodiment 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein the compound of formula I is a compound of formula (III-a) or (III-B):

wherein:

-the carbon represented by has S-stereochemistry or R-stereochemistry;

-ring B is a pyridyl ring;

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R ³Is methyl;

-k is 0, 1, 2, 3, 4, 5 or 6;

-q is 1 or 2;

-Z is of formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

40. The compound of embodiment 39, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring a is a phenyl ring, a pyridinyl ring, or a pyrazolyl ring, wherein ring a is optionally substituted with (R)¹)_mAnd (4) substitution.

41. The compound of embodiment 39 or 40, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is¹Independently selected from deuterium, C₁-C₂Alkyl and hydroxy, and m is 0 or 1.

42. The compound of any one of embodiments 39 to 41, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein n is 0.

43. A compound according to any one of embodiments 39 to 42, a pharmaceutically acceptable salt or prodrug thereofThe deuterated derivative of any one of the above, wherein ring D is (R)⁴)_qA substituted 5-membered heteroaryl ring.

44. The compound of any one of embodiments 39 to 42, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring D is substituted with (R) ⁴)_qA substituted pyrazolyl ring.

45. The compound of any one of embodiments 39 to 42, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring D is

Wherein

Indicating the point of attachment of ring D to ring B.

46. The compound of any one of embodiments 39 to 42, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring D is

Wherein

Indicating the point of attachment of ring D to ring B.

47. The compound of any one of embodiments 39 to 46, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁴Independently selected from oxo or- (Y)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

-each Y is independently selected from C (R)⁵)(R⁶) Radical (I)-O-and-NR^a-group in which- (Y)_k-R⁷Wherein the heteroatom is not bound to- (Y)_k-R⁷Wherein:

Each R ^aIndependently selected from hydrogen and C₁-C₂An alkyl group; and is

48. The compound of any one of embodiments 39 to 47, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R⁴Independently selected from oxo or- (Y)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

-R⁵and R⁶Each is atOptionally independently substituted with one or more groups selected from: c₁-C₂Alkyl radical, C₁-C₂Haloalkyl, halogen, hydroxy, C₁-C₂Alkoxy and C₁-C₂A haloalkoxy group; and is

49. The compound of any one of embodiments 39 to 47, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R ⁴Independently selected from oxo or-O- (Y)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4 or 5;

-R⁷Selected from hydrogen, halogen, cyano and optionally substituted by one or more groups selected fromSubstituted C₃-C₁₀Cycloalkyl groups: c₁-C₂Alkyl radical, C₁-C₂Haloalkyl, and halogen.

50. The compound of any one of embodiments 39 to 47, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R⁴Independently selected from:

wherein

Indication R⁴The point of attachment to loop D.

51. The compound of any one of embodiments 39 to 50, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein k is 3, 4, 5, or 6.

52. The compound of any one of embodiments 39 to 51, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein q is 1.

53. The compound of any one of embodiments 39 to 52, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein Z is formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Independently selected from hydrogen and deuterium; and is

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

54. The compound of any one of embodiments 39 to 52, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein Z is formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Independently selected from hydrogen and deuterium; and is

Each R^bIndependently selected from hydrogen and methyl.

55. The compound of any one of embodiments 39 to 52, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein Z is formula (L) _rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Independently selected from hydrogen and deuterium; and is

Each R^bIs hydrogen.

56. The compound of any one of embodiments 39 to 52, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein Z is formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Is hydrogen; and is

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

57. The compound of any one of embodiments 39 to 56, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is³Independently of CD₃.

58. The compound of embodiment 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein the compound of formula I is a compound of formula IV-a:

wherein:

-the carbon represented by has S-stereochemistry or R-stereochemistry;

X is O, NH or N (C)₁-C₄Alkyl groups);

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

-k is 0, 1, 2, 3, 4, 5 or 6;

-q is 1 or 2;

-Z is of formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

-each L is independently selected from C (R)⁸)(R⁹) Radical (I)-O-and-NR^b-a group wherein the heteroatom in Z is not bound to another heteroatom in Z, wherein:

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

59. The compound of embodiment 58, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is¹Independently selected from deuterium, C₁-C₂Alkyl and hydroxy, and m is 0 or 1.

60. The compound of embodiment 58 or 59, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein n is 0.

61. The compound of any one of embodiments 58 to 60, pharmaceutically acceptable salts thereof, or deuterated derivatives of any of the foregoing, wherein ring D is substituted with (R) ⁴)_qA substituted 5-membered heteroaryl ring.

62. The compound of any one of embodiments 58 to 60, pharmaceutically acceptable salts thereof, or deuterated derivatives of any of the foregoing, wherein ring D is substituted with (R)⁴)_qA substituted pyrazolyl ring.

63. The compound of any one of embodiments 58 to 60, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring D is

Wherein

Indicating the point of attachment of ring D to ring B.

64. The compound of any one of embodiments 58 to 60, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring D is

Wherein

Indicating the point of attachment of ring D to ring B.

65. The compound of any one of embodiments 58 to 64, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁴Independently selected from oxo or- (Y)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

-R⁵and R ⁶Each optionally independently substituted with one or more groups selected from: c₁-C₂Alkyl radical, C₁-C₂Haloalkyl, halogen, hydroxy, C₁-C₂Alkoxy and C₁-C₂A haloalkoxy group; and is

66. The compound of any one of embodiments 58 to 65, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁴Independently selected from oxo or- (R)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

67. The compound of any one of embodiments 58 to 66, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁴Independently selected from oxo or-O- (Y)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4 or 5;

-each Y is independently selected from C (R)⁵)(R⁶) The radicals, -O-and-NR^aA group in which-(Y)_k-R⁷Wherein the heteroatom is not bound to- (Y)_k-R⁷Wherein:

68. The compound of any one of embodiments 58 to 67, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is ⁴Independently selected from:

wherein

Indication R⁴The point of attachment to loop D.

69. The compound of any one of embodiments 58 to 68, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein k is 3, 4, 5, or 6.

70. The compound of any one of embodiments 58 to 69, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein q is 1.

71. A compound according to any one of embodiments 58 to 70, pharmaceutically acceptable salts thereof, or deuterated derivatives of any of the foregoing, wherein Z is formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Independently selected from hydrogen and deuterium; and is

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

72. A compound according to any one of embodiments 58 to 70, pharmaceutically acceptable salts thereof, or deuterated derivatives of any of the foregoing, wherein Z is formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

each R⁸And R ⁹Independently selected from hydrogen and deuterium; and is

Each R^bIndependently selected from hydrogen and methyl.

73. A compound according to any one of embodiments 58 to 70, pharmaceutically acceptable salts thereof, or deuterated derivatives of any of the foregoing, wherein Z is formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Independently selected from hydrogen and deuterium; and is

Each R^bIs hydrogen.

74. A compound according to any one of embodiments 58 to 70, pharmaceutically acceptable salts thereof, or deuterated derivatives of any of the foregoing, wherein Z is formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Is hydrogen; and is

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

75. The compound of any one of embodiments 58 to 74, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is³Independently of CD₃.

76. The compound of embodiment 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein the compound of formula 1 is a compound of formulae IV-B:

wherein:

-the carbon represented by has S-stereochemistry or R-stereochemistry;

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

-k is 0, 1, 2, 3, 4, 5 or 6;

-q is 1 or 2;

-r is 3 or 4;

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

77. The compound of embodiment 76, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁸And R⁹Independently selected from hydrogen, deuterium, halogen, C₁-C₂Alkyl, hydroxy, C₁-C₂Alkoxy and C₁-C₂A haloalkoxy group.

78. The compound of embodiment 76 or 77, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁸And R⁹Is H.

79. The compound of any one of embodiments 76 to 78, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is ¹Independently selected from deuterium, C₁-C₂Alkyl and hydroxy, and m is 0 or 1.

80. The compound of any one of embodiments 76 to 79, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein n is 0.

81. The compound of any one of embodiments 76 to 80, pharmaceutically acceptable salts thereof, or deuterated derivatives of any of the foregoing, wherein ring D is substituted with (R)⁴)_qA substituted 5-membered heteroaryl ring.

82. The compound of any one of embodiments 76 to 80, pharmaceutically acceptable salts thereof, or deuterated derivatives of any of the foregoing, wherein ring D is substituted with (R)⁴)_qA substituted pyrazolyl ring.

83. The compound of any one of embodiments 76 to 80, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring D is

Wherein

Indicating the point of attachment of ring D to ring B.

84. The compound of any one of embodiments 76 to 80, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring D is

Wherein

Indicating the point of attachment of ring D to ring B.

85. The compound of any one of embodiments 76 to 84, pharmaceutically acceptable salt thereof, or deuterated derivative of any one of the foregoing, wherein each R is⁴Independently selected from oxo or- (Y)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

86. The compound of any one of embodiments 76 to 84, pharmaceutically acceptable salt thereof, or deuterated derivative of any one of the foregoing, wherein each R is⁴Independently selected from oxo or- (Y)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

each R⁵And R⁶Independently selected from hydrogen, deuterium, halogen, hydroxy, C ₁-C₄Alkyl and C_3-5Cycloalkyl radicals, or R on the same carbon⁵And R⁶Together form C_3-5A cycloalkyl group;

Each R^aIndependently selectFrom hydrogen and C₁-C₂An alkyl group; and is

87. The compound of any one of embodiments 76 to 84, pharmaceutically acceptable salt thereof, or deuterated derivative of any one of the foregoing, wherein each R is⁴Independently selected from oxo or-O- (Y)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4 or 5;

88. The compound of any one of embodiments 76 to 84, pharmaceutically acceptable salt thereof, or deuterated derivative of any one of the foregoing, wherein each R is⁴Independently of each otherIs composed of

Wherein

Indication R⁴The point of attachment to loop D.

89. The compound of any one of embodiments 76 to 88, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein k is 3, 4, 5, or 6.

90. The compound of any one of embodiments 76 to 89, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein q is 1.

91. The compound of any one of embodiments 76 to 90, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Independently selected from hydrogen and deuterium; and is

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

92. The compound of any one of embodiments 76 to 90, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Is independently selected fromHydrogen and deuterium; and is

Each R^bIndependently selected from hydrogen and methyl.

93. The compound of any one of embodiments 76 to 90, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Independently selected from hydrogen and deuterium; and is

Each R^bIs hydrogen.

94. The compound of any one of embodiments 76 to 90, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Is hydrogen; and is

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

95. The compound of any one of embodiments 76 to 94, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is³Independently of CD₃。

96. The compound of embodiment 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein the compound of formula I is a compound of formulae IV-C:

wherein:

-the carbon represented by has S-stereochemistry or R-stereochemistry;

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

-k is 0, 1, 2, 3, 4, 5 or 6;

-R⁷Selected from hydrogen, halogen, cyano and C optionally substituted by one or more groups selected from ₃-C₁₀Cycloalkyl groups: c₁-C₂Alkyl radical, C₁-C₂Haloalkyl and halogen;

-q is 1 or 2;

-r is 3 or 4;

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

97. The compound of embodiment 96, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁸And R⁹Independently selected from hydrogen, deuterium, halogen, C₁-C₂Alkyl, hydroxy, C₁-C₂Alkoxy and C₁-C₂A haloalkoxy group.

98. The compound of embodiment 96 or 97, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁸And R⁹Is H.

99. The compound of any one of embodiments 96 to 98, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is¹Independently selected from deuterium, C₁-C₂Alkyl and hydroxy, and m is 0 or 1.

100. The compound of any one of embodiments 96 to 99, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein n is 0.

101. The compound of any one of embodiments 96 to 100, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁴Independently selected from oxo or- (Y) _k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

-each Y is independently selected from C (R)⁵)(R⁶) The radicals, -O-and-NR^a-group in which- (Y)_k-R⁷Wherein the heteroatom is not bound to- (Y)_k-R⁷In which the other hetero atom is bonded, wherein：

102. The compound of any one of embodiments 96 to 100, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁴Independently selected from oxo or- (Y)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

-R⁵and R⁶Each optionally independently substituted with one or more groups selected from: c₁-C₂Alkyl radical, C₁-C₂Haloalkyl, halogen, hydroxyBase, C₁-C₂Alkoxy and C₁-C₂A haloalkoxy group; and is

103. The compound of any one of embodiments 96 to 100, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁴Independently selected from oxo or-O- (Y)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4 or 5;

104. The compound of any one of embodiments 96 to 100, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁴Independently selected from:

wherein

Indication R⁴The point of attachment to loop D.

105. The compound of any one of embodiments 96 to 104, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein k is 3, 4, 5, or 6.

106. The compound of any one of embodiments 96 to 105, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein q is 1.

107. The compound of any one of embodiments 96 to 106, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Independently selected from hydrogen and deuterium; and is

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

108. The compound of any one of embodiments 96 to 106, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Independently selected from hydrogen and deuterium; and is

Each R^bIndependently selected from hydrogen and methyl.

109. The compound of any one of embodiments 96 to 106, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Independently selected from hydrogen and deuterium; and is

Each R^bIs hydrogen.

110. The compound of any one of embodiments 96 to 106, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Is hydrogen; and is

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

111. The compound of any one of embodiments 96 to 110, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is³Independently of CD₃.

112. The compound of embodiment 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein the compound of formula I is a compound of formula V-a:

wherein:

-the carbon represented by has S-stereochemistry or R-stereochemistry;

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

-k is 0, 1, 2, 3, 4, 5 or 6;

-q is 1 or 2;

-Z is of formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

113. The compound of embodiment 112, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is¹Independently selected from deuterium, C₁-C₂Alkyl and hydroxy, and m is 0 or 1.

114. The compound of embodiment 112 or 113, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein n is 0.

115. The compound of any one of embodiments 112 to 114, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring D is substituted with (R)⁴)_qA substituted 5-membered heteroaryl ring.

116. The compound of any one of embodiments 112 to 114, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring D is substituted with (R) ⁴)_qA substituted pyrazolyl ring.

117. The compound of any one of embodiments 112 to 114, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring D is

Wherein

Indicating the point of attachment of ring D to ring B.

118. The compound of any one of embodiments 112 to 117, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring D is

Wherein

Indicating the point of attachment of ring D to ring B.

119. The compound of any one of embodiments 112 to 118, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁴Independently selected from oxo or- (Y)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

120. The compound of any one of embodiments 112 to 118, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁴Independently selected from oxo or- (Y)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

121. The compound of any one of embodiments 112 to 118, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is ⁴Independently selected from oxo or-O- (Y)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4 or 5;

122. The compound of any one of embodiments 112 to 118, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁴Independently selected from:

wherein

Indication R⁴The point of attachment to loop D.

123. The compound of any one of embodiments 112 to 122, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein k is 3, 4, 5, or 6.

124. The compound of any one of embodiments 112 to 123, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein q is 1.

125. The compound of any one of embodiments 112 to 124, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein Z is formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Independently selected from hydrogen and deuterium; and is

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

126. The compound of any one of embodiments 112 to 124, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein Z is formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Independently selected from hydrogen and deuterium; and is

Each R^bIndependently selected from hydrogen and methyl.

127. The compound of any one of embodiments 112 to 124, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein Z is formula (L) _rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Independently selected from hydrogen and deuterium; and is

Each R^bIs hydrogen.

128. The compound of any one of embodiments 112 to 124, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein Z is formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Is hydrogen; and is

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

129. The compound of any one of embodiments 112 to 128, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is³Independently of CD₃.

130. The compound of embodiment 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein the compound of formula I is a compound of formula V-B:

wherein:

-the carbon represented by has S-stereochemistry or R-stereochemistry;

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

-k is 0, 1, 2, 3, 4, 5 or 6;

-q is 1 or 2;

-r is 3, 4 or 5; and is

131. The compound of embodiment 130, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁸And R⁹Independently selected from hydrogen, deuterium, halogen, C₁-C₂Alkyl, hydroxy, C₁-C₂Alkoxy and C₁-C₂A haloalkoxy group.

132. The compound of embodiment 130 or 131, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁸And R⁹Is H.

133. The compound of any one of embodiments 130 to 132, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is¹Independently selected from deuterium, C₁-C₂Alkyl radicalAnd a hydroxyl group, and m is 0 or 1.

134. The compound of any one of embodiments 130 to 133, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein n is 0.

135. The compound of any one of embodiments 130 to 134, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring D is substituted with (R) ⁴)_qA substituted 5-membered heteroaryl ring.

136. The compound of any one of embodiments 130 to 134, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring D is substituted with (R)⁴)_qA substituted pyrazolyl ring.

137. The compound of any one of embodiments 130 to 134, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring D is

Wherein

Indicating the point of attachment of ring D to ring B.

138. The compound of any one of embodiments 130 to 137, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring D is

Wherein

Indicating the point of attachment of ring D to ring B.

139. The compound of any one of embodiments 130 to 138, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁴Independently selected from oxo or- (Y)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

140. The compound of any one of embodiments 130 to 138, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁴Independently selected from oxo or- (Y)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

each R⁵And R⁶Independently selected from hydrogen, deuterium, halogen, hydroxy, C₁-C₄Alkyl and C_3-5Cycloalkyl radicals, or the sameR on carbon⁵And R⁶Together form C_3-5A cycloalkyl group;

Each R^aIndependently selected from hydrogen and C ₁-C₂An alkyl group; and is

141. The compound of any one of embodiments 130 to 138, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁴Independently selected from oxo or-O- (Y)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4 or 5;

142. The compound of any one of embodiments 130 to 138, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is ⁴Independently selected from:

wherein

Indication R⁴The point of attachment to loop D.

143. The compound of any one of embodiments 130 to 142, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein k is 3, 4, 5, or 6.

144. The compound of any one of embodiments 130 to 143, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein q is 1.

145. The compound of any one of embodiments 130 to 144, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein:

-r is 3, 4 or 5; and is

Each R⁸And R⁹Independently selected from hydrogen and deuterium.

146. The compound of any one of embodiments 130 to 144, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein:

-r is 3, 4 or 5; and is

Each R⁸And R⁹Is hydrogen.

147. The compound of any one of embodiments 130 to 144, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein:

-r is 3, 4 or 5; and is

Each R⁸And R⁹Is deuterium.

148. The compound of any one of embodiments 130 to 144, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein:

-r is 3 or 4; and is

Each R⁸And R⁹Is hydrogen.

149. The compound of any one of embodiments 130 to 148, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is³Independently of CD₃。

150. The compound of embodiment 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein the compound of formula I is a compound of formula VI-a or VI-B:

wherein:

-the carbon represented by has S-stereochemistry or R-stereochemistry;

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

-k is 0, 1, 2, 3, 4, 5 or 6;

-q is 1 or 2;

-Z is of formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

151. The compound of embodiment 150, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is¹Independently selected from deuterium, C₁-C₂Alkyl and hydroxy, and m is 0 or 1.

152. The compound of

embodiment

150 or 151, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein n is 0.

153. The compound of any one of embodiments 150 to 152, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring D is substituted with (R)⁴)_qA substituted 5-membered heteroaryl ring.

154. The compound of any one of embodiments 150 to 152, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring D is substituted with (R)⁴)_qA substituted pyrazolyl ring.

155. The compound of any one of embodiments 150 to 152, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring D is

Wherein

Indicating the point of attachment of ring D to ring B.

156. The compound of any one of embodiments 150 to 152, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring D is

Wherein

Indicating the point of attachment of ring D to ring B.

157. The compound of any one of embodiments 150 to 156, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is ⁴Independently selected from oxo or- (Y)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

158. The compound of any one of embodiments 150 to 156, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁴Independently selected from oxo or- (Y)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

-R⁷Selected from hydrogen, halogen, cyano andc optionally substituted by one or more groups selected from₃-C₁₀Cycloalkyl groups: c₁-C₂Alkyl radical, C₁-C₂Haloalkyl, and halogen.

159. The compound of any one of embodiments 150 to 156, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁴Independently selected from oxo or-O- (Y)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4 or 5;

160. The compound of any one of embodiments 150 to 156, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁴Independently selected from:

wherein

Indication R⁴The point of attachment to loop D.

161. The compound of any one of embodiments 150 to 160, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein k is 3, 4, 5, or 6.

162. The compound of any one of embodiments 150 to 161, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein q is 1.

163. The compound of any one of embodiments 150 to 162, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein Z is formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

Each R⁸And R⁹Independently selected from hydrogen and deuterium; and is

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

164. The compound of any one of embodiments 150 to 162, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein Z is formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Independently selected from hydrogen and deuterium; and is

Each R^bIndependently selected from hydrogen and methyl.

165. The compound of any one of embodiments 150 to 162, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein Z is formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Independently selected from hydrogen and deuterium; and is

Each R^bIs hydrogen.

166. The compound of any one of embodiments 150 to 162, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein Z is formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

-each L is independently selected from C (R) ⁸)(R⁹) The radicals, -O-and-NR^b-a group wherein the heteroatom in Z is not bound to another heteroatom in Z, wherein:

each R⁸And R⁹Is hydrogen; and is

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

167. A compound according to any one of embodiments 150 to 166, a pharmaceutically acceptable salt thereofOr a deuterated derivative of any of the foregoing, wherein each R³Independently of CD₃。

168. The compound of embodiment 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein the compound of formula I is a compound of formula VI-C or VI-D:

wherein:

-the carbon represented by has S-stereochemistry or R-stereochemistry;

x is O, NH or N (C)₁-C₄Alkyl groups);

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

each R⁴Independently selected from the group consisting of halogen, oxo, hydroxy, cyano and- (Y) _k-R⁷A group, or optionally, two R⁴Together with the atoms to which they are attached form a 5-to 6-membered cycloalkyl or heterocyclyl ring optionally and independently substituted with one or more groups selected from: halogen, C₁-C₂Alkyl, haloalkyl, hydroxy, C₁-C₂Alkoxy radicalAnd C₁-C₂Haloalkoxy, wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

-q is 1 or 2;

-r is 3 or 4; and is

Each R⁸And R⁹Independently selected from hydrogen, halogen, C₁-C₂Alkyl, hydroxy, C₁-C₂Alkoxy and C ₁-C₂A haloalkoxy group.

169. The compound of embodiment 168, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁸And R⁹Independently selected from hydrogen, deuterium, halogen, C₁-C₂Alkyl, hydroxy, C₁-C₂Alkoxy and C₁-C₂A haloalkoxy group.

170. The compound of embodiment 169 or 169, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R⁸And R⁹Is H.

171. The compound of any one of embodiments 168 to 170, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is¹Independently selected from deuterium, C₁-C₂Alkyl and hydroxy, and m is 0 or 1.

172. The compound of any one of embodiments 168 to 171, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein n is 0.

173. The compound of any one of embodiments 168 to 172, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring D is substituted with (R)⁴)_qA substituted 5-membered heteroaryl ring.

174. The compound of any one of embodiments 168 to 172, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring D is substituted with (R)⁴)_qA substituted pyrazolyl ring.

175. The compound of any one of embodiments 168 to 172, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring D is

Wherein

Indicating the point of attachment of ring D to ring B.

176. The compound of any one of embodiments 168 to 172, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring D is

Wherein

Indicating the point of attachment of ring D to ring B.

177. The compound of any one of embodiments 168 to 172, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁴Independently selected from oxo or- (Y)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

-each Y is independently selected from C (R)₅)(R₆) The radicals, -O-and-NR^a-group in which- (Y)_k-R⁷Wherein the heteroatom is not bound to- (Y)_k-R⁷Wherein:

-R⁷Selected from hydrogen, halogen, cyano and C optionally substituted by one or more groups selected from₃-C₁₀Cycloalkyl groups: c₁-C₂Alkyl radical, C ₁-C₂Haloalkyl, and halogen.

178. The compound of any one of embodiments 168 to 176, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁴Independently selected from oxo or- (Y)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

179. The compound of any one of embodiments 168 to 176, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁴Independently selected from oxo or-O- (Y)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4 or 5;

each R⁵And R⁶Independently selected from hydrogen, deuterium, halogen,Hydroxy, C₁-C₄Alkyl and C_3-5Cycloalkyl radicals, or R on the same carbon⁵And R⁶Together form C_3-5Cycloalkyl or oxo;

180. The compound of any one of embodiments 168 to 176, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁴Independently selected from:

wherein

Indication R⁴The point of attachment to loop D.

181. The compound of any one of embodiments 168 to 180, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein k is 3, 4, 5, or 6.

182. The compound of any one of embodiments 168 to 181, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein q is 1.

183. The compound of any one of embodiments 168 to 182, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein:

-r is 3, 4 or 5; and is

Each R⁸And R⁹Independently selected from hydrogen and deuterium.

184. The compound of any one of embodiments 168 to 182, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein:

-r is 3, 4 or 5; and is

Each R⁸And R⁹Is hydrogen.

185. The compound of any one of embodiments 168 to 182, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein:

-r is 3, 4 or 5; and is

Each R⁸And R⁹Is deuterium.

186. The compound of any one of embodiments 168 to 182, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein:

-r is 3 or 4; and is

Each R⁸And R⁹Is hydrogen.

187. The compound of any one of embodiments 168 to 186, wherein each R is³Independently of CD₃。

188. The compound of any one of embodiments 20 to 57, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein the carbon represented by x of formula (II-a) or (III-a) has S-stereochemistry, and wherein the carbon represented by x of formula (II-B) or (III-B) has R-stereochemistry.

189. The compound of any one of embodiments 58 to 187, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein the carbon represented by any one of formulae (IV-a), (IV-B), (IV-C), (V-a), (V-B), (VI-a), (VI-B), (VI-C), and (VI-D) has S-stereochemistry.

190. The compound of any one of embodiments 58 to 187, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein the carbon represented by any one of formulae (IV-a), (IV-B), (IV-C), (V-a), (V-B), (VI-a), (VI-B), (VI-C), and (VI-D) has R-stereochemistry.

191. A compound selected from compound nos. 1-302 depicted in fig. 1, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing.

192. A compound selected from compounds No. 303-309 depicted in figure 1, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing.

193. A compound selected from:

pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing.

194. A pharmaceutical composition comprising: at least one compound selected from a compound according to any one of embodiments 1 to 191, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, and optionally one or more of the following:

(a) Compound II:

a pharmaceutically acceptable salt thereof or a deuterated derivative of any one of the foregoing;

(b) compound III:

a pharmaceutically acceptable salt thereof or a deuterated derivative of any one of the foregoing; and

(c) a pharmaceutically acceptable carrier.

195. A method of treating cystic fibrosis comprising administering to a patient in need thereof a compound according to any one of embodiments 1 to 191 or a pharmaceutical composition according to embodiment 194.

196. Use of at least one compound selected from a compound according to any one of embodiments 1 to 191, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, and optionally one or more of the following:

(a) compound II:

(b) compound III:

it is used for the treatment of cystic fibrosis.

197. A compound of formula (X):

a salt thereof or a deuterated derivative of any of the foregoing,

wherein:

-Q^ais halogen;

-ring B is a pyridyl ring;

-X isO, NH or N (C)₁-C₄Alkyl groups);

each R¹Independently selected from C₁-C₂Alkyl radical, C ₁-C₂Alkoxy radical, C₁-C₂Haloalkyl, C₁-C₂Haloalkoxy, halogen, cyano and hydroxy;

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

-Z is of formula (L)_rThe divalent linker of (1), wherein:

-r is 1, 2, 3, 4, 5 or 6;

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

198. A compound of formula (Y):

a salt thereof or a deuterated derivative of any of the foregoing,

wherein:

-Q^bis halogen;

-R¹⁰is hydrogen or a protecting group;

-ring B is a pyridyl ring;

x is O, NH or N (C)₁-C₄Alkyl groups);

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

-k is 0, 1, 2, 3, 4, 5 or 6;

-q is 1, 2, 3 or 4; and is

-Z is of formula (L)_rThe divalent linker of (1), wherein:

-r is 1, 2, 3, 4, 5 or 6;

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

199. A process for preparing a compound of formula (I):

a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, comprising:

reacting a compound of formula (Y-I):

NH group of ring C and Q of ring B of a salt thereof or a deuterated derivative of any of the foregoing^bRadical coupling, wherein:

-Q^bis halogen;

-ring B is a pyridyl ring;

x is O, NH or N (C)₁-C₄Alkyl groups);

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

-k is 0, 1, 2, 3, 4, 5 or 6;

-each Y is independently selected from C (R)⁵)(R⁶) A group, -O-and-NR^a-group in which- (Y)_k-R⁷Wherein the heteroatom is not bound to- (Y)_k-R⁷Wherein:

-q is 1, 2, 3 or 4; and is

-Z is of formula (L)_rThe divalent linker of (1), wherein:

-r is 1, 2, 3, 4, 5 or 6;

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group;

to form a compound of formula (I), a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing.

200. The method of embodiment 198 wherein the coupling is carried out in the presence of a base.

201. A process for preparing a compound of formula (Y):

a method of a salt thereof or a deuterated derivative of any of the foregoing, comprising:

reacting a compound of formula (a), a salt thereof, or a deuterated derivative of any of the foregoing with a compound of formula (B), a salt thereof, or a deuterated derivative of any of the foregoing to form a compound of formula (Y), a salt thereof, or a deuterated derivative of any of the foregoing:

and

optionally deprotecting the N-protecting group of ring C of formula (Y) wherein

Q^bIs halogen;

r of formula (Y)¹⁰Is hydrogen or an N-protecting group;

r of formula (B) ¹⁰Is an N-protecting group, and

ring A, ring B, ring D, X, R¹、m、R²、n、R³、R⁴、q、Z、R¹⁰And wherein the variables are as set forth in embodiment 1.

202. The method of embodiment 201, wherein said reacting the compound of formula (a), a salt thereof, or a deuterated derivative of any one of the foregoing with the compound of formula (B), a salt thereof, or a deuterated derivative of any one of the foregoing is carried out in the presence of a base.

203. The method of embodiment 201 wherein the reacting the compound of formula (a), a salt thereof, or a deuterated derivative of any of the foregoing with the compound of formula (B), a salt thereof, or a deuterated derivative of any of the foregoing comprises reacting the compound of formula (a), a salt thereof, or a deuterated derivative of any of the foregoing with a coupling agent and then with the compound of formula (B), a salt thereof, or a deuterated derivative of any of the foregoing in the presence of a base.

204. A process for preparing a compound of formula (Y-2):

a method of a salt thereof or a deuterated derivative of any one of the foregoing, wherein:

-Q^bis halogen;

-ring B is a pyridyl ring;

x is O, NH or N (C)₁-C₄Alkyl groups);

each R¹Independently selected from C₁-C₂Alkyl radical, C₁-C₂Alkoxy radical, C ₁-C₂Haloalkyl, C₁-C₂Haloalkoxy, halogen, cyano and hydroxy;

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

-k is 0, 1, 2, 3, 4, 5 or 6;

-q is 1, 2, 3 or 4;

-r is 1, 2, 3, 4 or 5;

-R¹⁰Is hydrogen or a protecting group;

the method comprises reacting a compound of formula (a), a salt thereof, or a deuterated derivative of any of the foregoing with a compound of formula (B-2), a salt thereof, or a deuterated derivative of any of the foregoing to form the compound of formula (Y-2), a salt thereof, or a deuterated derivative of any of the foregoing:

205. the method of embodiment 204, wherein said reacting the compound of formula (a), a salt thereof, or a deuterated derivative of any of the foregoing with the compound of formula (B-2), a salt thereof, or a deuterated derivative of any of the foregoing is carried out in the presence of a base.

206. The method of embodiment 205 wherein said reacting the compound of formula (a), a salt thereof, or a deuterated derivative of any of the foregoing with the compound of formula (B-2), a salt thereof, or a deuterated derivative of any of the foregoing comprises reacting the compound of formula (a), a salt thereof, or a deuterated derivative of any of the foregoing with a coupling agent and then with the compound of formula (B-2), a salt thereof, or a deuterated derivative of any of the foregoing in the presence of a base.

207. The method of any one of embodiments 204 to 206, further comprising reacting a compound of formula (D), a salt thereof, or a deuterated derivative of any one of the foregoing with a compound of formula (E-2), a salt thereof, or a deuterated derivative of any one of the foregoing to form the compound of formula (B-2), a salt thereof, or a deuterated derivative of any one of the foregoing:

wherein R is^dIs halogen.

208. A process for preparing a compound of formula (Y-3):

reacting a compound of formula (a), a salt thereof, or a deuterated derivative of any of the foregoing with a compound of formula (B-3), a salt thereof, or a deuterated derivative of any of the foregoing to form the compound of formula (Y-3), a salt thereof, or a deuterated derivative of any of the foregoing:

209. the method of embodiment 208 wherein said reacting the compound of formula (a), a salt thereof, or a deuterated derivative of any of the foregoing with the compound of formula (B-3), a salt thereof, or a deuterated derivative of any of the foregoing is carried out in the presence of a base.

210. The method of embodiment 208 wherein said reacting the compound of formula (a), a salt thereof, or a deuterated derivative of any of the foregoing with the compound of formula (B-3), a salt thereof, or a deuterated derivative of any of the foregoing comprises reacting the compound of formula (a), a salt thereof, or a deuterated derivative of any of the foregoing with a coupling agent and then with the compound of formula (B-3), a salt thereof, or a deuterated derivative of any of the foregoing in the presence of a base.

211. The method of any one of embodiments 208 to 210, further comprising reacting a compound of formula (D), a salt thereof, or a deuterated derivative of any one of the foregoing with a compound of formula (E-3), a salt thereof, or a deuterated derivative of any one of the foregoing to form the compound of formula (B-3), a salt thereof, or a deuterated derivative of any one of the foregoing:

212. a process for preparing a compound of formula (I):

a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring D is

The method comprises the following steps:

reacting a compound of formula (X), a salt thereof, or a deuterated derivative of any of the foregoing with a compound of formula (Z-1), a salt thereof, or a deuterated derivative of any of the foregoing:

wherein:

-Q^ais halogen;

-ring B is a pyridyl ring;

x is O, NH or N (C)₁-C₄Alkyl groups);

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

-k is 0, 1, 2, 3, 4, 5 or 6;

each R⁵And R⁶Independently selected from hydrogen, halogen, hydroxy, C1-C4 alkyl and C_3-5Cycloalkyl radicals, or R on the same carbon⁵And R⁶Together form C_3-5Cycloalkyl or oxo;

-q is 1, 2, 3 or 4; and is

-Z is of formula (L)_rThe divalent linker of (1), wherein:

-r is 1, 2, 3, 4, 5 or 6;

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

213. A process for preparing a compound of formula (IV-C):

reacting a compound of formula (X-1), a salt thereof, or a deuterated derivative of any of the foregoing with a compound of formula (Z-1), a salt thereof, or a deuterated derivative of any of the foregoing:

wherein:

-Q^ais halogen;

-the carbon represented by has S-stereochemistry or R-stereochemistry;

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

-k is 0, 1, 2, 3, 4, 5 or 6;

-q is 1 or 2;

-r is 3 or 4;

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

214. The compound of any one of embodiments 1 to 190, wherein the compound is in the form of a pharmaceutically acceptable salt.

215. The compound of embodiment 214, wherein said pharmaceutically acceptable salt is a sodium, calcium or potassium salt.

216. The compound of embodiment 215, wherein said pharmaceutically acceptable salt is a calcium salt.

217. The compound of embodiment 191, wherein the compound is in the form of a pharmaceutically acceptable salt.

218. The compound of embodiment 217, wherein the pharmaceutically acceptable salt is a sodium, calcium or potassium salt.

219. The compound of embodiment 218, wherein the pharmaceutically acceptable salt is a calcium salt.

220. The compound of embodiment 192, wherein the compound is in the form of a pharmaceutically acceptable salt.

221. The compound of embodiment 220, wherein the pharmaceutically acceptable salt is a sodium, calcium or potassium salt.

222. The compound of embodiment 221, wherein said pharmaceutically acceptable salt is a calcium salt.

223. The compound of embodiment 193, wherein the compound is in the form of a pharmaceutically acceptable salt.

224. The compound of embodiment 223, wherein the pharmaceutically acceptable salt is a sodium, calcium or potassium salt.

225. The compound of embodiment 224, wherein the pharmaceutically acceptable salt is a calcium salt.

226. The compound of embodiment 193, wherein the compound is

227. The compound of embodiment 193, wherein the compound is in the form of the calcium salt of:

228. the compound of embodiment 193, wherein the compound is

229. The compound of embodiment 193, wherein the compound is in the form of the calcium salt of:

230. the compound of embodiment 193, wherein the compound is

231. The compound of embodiment 193, wherein the compound is in the form of the calcium salt of:

232. the compound of embodiment 193, wherein the compound is

233. The compound of embodiment 193, wherein the compound is in the form of the calcium salt of:

234. the compound of embodiment 193, wherein the compound is

235. The compound of embodiment 193, wherein the compound is in the form of the calcium salt of:

236. The compound of embodiment 193, wherein the compound is

237. The compound of embodiment 193, wherein the compound is in the form of the calcium salt of:

238. the compound of embodiment 193, wherein the compound is

239. The compound of embodiment 193, wherein the compound is in the form of the calcium salt of:

240. the compound of embodiment 193, wherein the compound is

241. The compound of embodiment 193, wherein the compound is in the form of the calcium salt of:

242. the compound of embodiment 193, wherein the compound is

243. The compound of embodiment 193, wherein the compound is in the form of the calcium salt of:

244. the compound of embodiment 193, wherein the compound is

245. The compound of embodiment 193, wherein the compound is in the form of the calcium salt of:

246. the method of treating cystic fibrosis of embodiment 195, wherein the compound is in the form of a pharmaceutically acceptable salt.

247. The method of embodiment 246, wherein the pharmaceutically acceptable salt is a sodium, calcium, or potassium salt.

248. The method of embodiment 247, wherein the pharmaceutically acceptable salt is a calcium salt.

249. A method of treating cystic fibrosis comprising administering a compound of embodiment 192 to a patient in need thereof.

250. A method of treating cystic fibrosis comprising administering to a patient in need thereof a compound of any one of embodiments 193 or 226 to 245.

251. The method of treating cystic fibrosis of

embodiment

249 or 250, wherein the compound is in the form of a pharmaceutically acceptable salt.

252. The method of embodiment 251, wherein the pharmaceutically acceptable salt is a sodium, calcium or potassium salt.

253. The method of embodiment 252, wherein the pharmaceutically acceptable salt is a calcium salt.

254. A method of treating cystic fibrosis comprising administering to a patient in need thereof a compound of any one of embodiments 1 to 190, wherein the compound is administered in combination with compound III or a pharmaceutically acceptable salt or deuterated derivative thereof.

255. A method of treating cystic fibrosis comprising administering a compound of embodiment 191 to a patient in need thereof, wherein the compound is administered in combination with compound III or a pharmaceutically acceptable salt or deuterated derivative thereof.

256. A method of treating cystic fibrosis comprising administering a compound according to embodiment 192 to a patient in need thereof, wherein the compound is administered in combination with compound III or a pharmaceutically acceptable salt or deuterated derivative thereof.

257. A method of treating cystic fibrosis comprising administering to a patient in need thereof a compound of any one of embodiments 193 or 226 to 245, wherein the compound is administered in combination with compound III or a pharmaceutically acceptable salt or deuterated derivative thereof.

258. The method of any one of embodiments 254 to 257, wherein the deuterated derivative of compound III is compound III-d.

259. A method of treating cystic fibrosis comprising administering to a patient in need thereof a compound of any one of embodiments 1 to 190, wherein the compound is administered in combination with (a) compound II and (b) compound III or a deuterated derivative thereof.

260. A method of treating cystic fibrosis comprising administering to a patient in need thereof a compound of embodiment 191 wherein the compound is administered in combination with (a) compound II and (b) compound III or a deuterated derivative thereof.

261. A method of treating cystic fibrosis comprising administering a compound of embodiment 192 to a patient in need thereof, wherein the compound is administered in combination with (a) compound II and (b) compound III or a deuterated derivative thereof.

262. A method of treating cystic fibrosis comprising administering to a patient in need thereof a compound of any one of embodiments 193 or 226 to 245, wherein the compound is administered in combination with (a) compound II and (b) compound III or a deuterated derivative thereof.

263. The method of any one of embodiments 259 to 262, wherein the deuterated derivative of compound III is compound III-d.

264. The method of any one of embodiments 254 to 262, wherein the compound is in the form of a pharmaceutically acceptable salt.

265. The method of embodiment 264, wherein the pharmaceutically acceptable salt is a sodium, calcium or potassium salt.

266. The method of embodiment 265, wherein said pharmaceutically acceptable salt is a calcium salt.

267. A pharmaceutical composition comprising a compound according to embodiment 191 and a pharmaceutically acceptable carrier.

268. A pharmaceutical composition comprising a compound according to embodiment 192 and a pharmaceutically acceptable carrier.

269. A pharmaceutical composition comprising a compound according to any one of embodiments 193 or 226 to 245 and a pharmaceutically acceptable carrier.

270. The pharmaceutical composition of any one of embodiments 267 to 269, wherein the compound is in the form of a pharmaceutically acceptable salt.

271. The pharmaceutical composition of embodiment 270, wherein said pharmaceutically acceptable salt is a sodium, calcium, or potassium salt.

272. The pharmaceutical composition of embodiment 271, wherein the pharmaceutically acceptable salt is a calcium salt.

273. The pharmaceutical composition of any one of embodiments 267-272, further comprising compound III or a pharmaceutically acceptable salt or deuterated derivative thereof.

274. The pharmaceutical composition of embodiment 273, wherein the deuterated derivative of compound III is compound III-d.

275. The pharmaceutical composition of any one of embodiments 267-272, further comprising (a) compound II and (b) compound III or a deuterated derivative thereof.

276. The pharmaceutical composition of embodiment 275, wherein the deuterated derivative of compound III is compound III-d.

277. A compound according to any one of embodiments 1 to 190 for use in the treatment of cystic fibrosis.

278. The compound of embodiment 191 for use in the treatment of cystic fibrosis.

279. The compound of embodiment 192 for use in the treatment of cystic fibrosis.

280. A compound according to any one of embodiments 193 or 226 to 245 for use in the treatment of cystic fibrosis.

281. The compound for use according to any one of embodiments 277 to 280, wherein the compound is in the form of a pharmaceutically acceptable salt.

282. A compound for use as described in embodiment 281 wherein the pharmaceutically acceptable salt is a sodium, calcium or potassium salt.

283. The compound for use of embodiment 282, wherein the pharmaceutically acceptable salt is a calcium salt.

284. The compound for use of any one of embodiments 277 to 283, wherein the treatment further comprises administering compound III.

285. The compound for use of any one of embodiments 277 to 283, wherein the treatment further comprises administering compound III-d.

286. The compound for use of any one of embodiments 277 to 283, wherein the treatment further comprises administering compound II and compound III.

287. The compound of any one of embodiments 277 to 283, wherein the treatment further comprises administering compound II and compound III-d.

Other embodiments include:

A. a compound of formula I:

B. a pharmaceutically acceptable salt of a compound of formula I:

C. a pharmaceutical composition comprising:

(i) a compound of formula I:

and

(ii) a pharmaceutically acceptable carrier.

D. The pharmaceutical composition of embodiment C, further comprising compound II:

E. the pharmaceutical composition of embodiment C, further comprising a pharmaceutically acceptable salt of compound II:

F. the pharmaceutical composition of embodiment C, further comprising compound III:

G. the pharmaceutical composition of embodiment C, further comprising a pharmaceutically acceptable salt of compound III:

H. The pharmaceutical composition of embodiment D, further comprising compound III:

I. the pharmaceutical composition of embodiment D, further comprising a pharmaceutically acceptable salt of compound III:

J. the pharmaceutical composition of embodiment E, further comprising compound III:

K. the pharmaceutical composition of embodiment E, further comprising a pharmaceutically acceptable salt of compound III:

l. a pharmaceutical composition comprising:

(A) a pharmaceutically acceptable salt of a compound of formula I:

and

(B) a pharmaceutically acceptable carrier.

A pharmaceutical composition according to embodiment L, further comprising compound II:

a pharmaceutical composition according to embodiment L, further comprising a pharmaceutically acceptable salt of compound II:

o. a pharmaceutical composition according to embodiment L, further comprising compound III:

p. a pharmaceutical composition according to embodiment L, further comprising a pharmaceutically acceptable salt of compound III:

q. the pharmaceutical composition of embodiment M, further comprising compound III:

r. a pharmaceutical composition according to embodiment M, further comprising a pharmaceutically acceptable salt of compound III:

s. the pharmaceutical composition of embodiment M, further comprising compound III:

t. a pharmaceutical composition according to embodiment M, further comprising a pharmaceutically acceptable salt of compound III:

A method of treating cystic fibrosis comprising administering a compound of formula I to a patient in need thereof

A method of treating cystic fibrosis comprising administering to a patient in need thereof a pharmaceutically acceptable salt of a compound of formula I

A method of treating cystic fibrosis comprising administering to a patient in need thereof a pharmaceutical composition comprising:

(A) a compound of formula I:

and

(B) a pharmaceutically acceptable carrier.

a pharmaceutically acceptable salt of a compound of formula I:

and

a pharmaceutically acceptable carrier.

General Experimental procedure

The following summarizes the definitions of certain abbreviations used in the examples below:

boc anhydride ((Boc)₂O): di-tert-butyl dicarbonate

CDI: carbonyl diimidazoles

DABCO: 1, 4-diazabicyclo [2.2.2] octane

DBU: 1, 8-diazabicyclo (5.4.0) undec-7-ene

DCM: methylene dichloride

The DIAD: diisopropyl azodicarboxylate

DIEA (DIPEA; N, N-diisopropylethylamine)

DMA: n, N-dimethyl acetamide

DMF: n, N-dimethylformamide

DMSO, DMSO: dimethyl sulfoxide

Et 2O: diethyl ether

EtOH: ethanol

HATU: 1- [ bis (dimethylamino) methylene ] -1H-1, 2, 3-triazolo [4, 5-b ] pyridinium 3-oxide hexafluorophosphate

IPA: isopropanol (I-propanol)

MeOH: methanol

NMP: n-methyl-2-pyrrolidone

MTBE: methyl tert-butyl ether

TBS-Cl: tert-butyldimethylsilyl chloride

TFA: trifluoroacetic acid

THF: tetrahydrofuran (THF)

p-TsOH: p-toluenesulfonic acid

TPPO-DIAD complex: compound of triphenylphosphine oxide and diisopropyl azodicarboxylate

Unless otherwise stated, reagents and starting materials were obtained from commercial sources and used without purification proton and carbon NMR spectra at 400 and 100MHz, respectively¹H and¹³one-dimensional proton and carbon spectra were obtained using a broadband observation (BBFO) probe with 20Hz sample rotation at 0.1834 and 0.9083Hz/Pt digital resolution, respectively, all proton and carbon spectra were obtained by temperature control at 30 ℃ using standard previously disclosed pulse sequences and conventional processing parameters₁₈Column (50X 2.1 mm, 1.7 μm particles) (pn: 186002350) and determination of a double gradient run of 1-99% mobile phase B over 3.0 minutes ₂O(0.05％CF₃CO₂H) In that respect Mobile phase B ═ CH₃CN(0.035％ CF₃CO₂H) Flow rate 1.2mL/min, injection volumeLow resolution mass spectra are reported as obtained using a single quadrupole mass spectrometer equipped with an electrospray ionization (ESI) source capable of achieving 0.1Da mass accuracy and 1000 minimum resolution (units of no resolution) over the entire detection range [ M + H ℃. (iv) and a final purity of 60 ℃. the final purity is calculated by averaging the area under the curve (AUC) of two UV traces (220nm, 254nm)]⁺And (3) a substance. Optical purity of (2S) -2, 4-dimethyl-4-nitro-pentanoic acid methyl ester analysis by chiral Gas Chromatography (GC) on an Agilent 7890A/MSD 5975C instrument using a Restek Rt- β DEXcst (30m × 0.25mm × 0.25um _ df) column at a flow rate (H) of 2.0mL/min₂Carrier gas) at an injection temperature of 220 c and an oven temperature of 120 c over a period of 15 minutes.

Synthetic examples

Synthesis of compound II: (R) -1- (2, 2-difluorobenzo [ d ] [1, 3] dioxol-5-yl) -N- (1- (2, 3-dihydroxypropyl) -6-fluoro-2- (1-hydroxy-2-methylpropan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide

Step 1: benzyl (R) -2- (1- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) -6-fluoro-5-nitro-1H-indol-2-yl) -2-methylpropionate and ((S) -2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl 2- (1- (((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) -6-fluoro-5-nitro-1H-indol-2-yl) -2-methylpropionate

Cesium carbonate (8.23g, 25.3mmol) was added to a mixture of benzyl 2- (6-fluoro-5-nitro-1H-indol-2-yl) -2-methylpropionate (3.0g, 8.4mmol) and (S) - (2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl 4-methylbenzenesulfonate (7.23g, 25.3mmol) in DMF (N, N-dimethylformamide) (17 mL.) the reaction was stirred at 80 ℃ under a nitrogen atmosphere for 46 hours then the mixture was partitioned between ethyl acetate and water₄The crude product (a viscous brown oil containing the two products shown above) was dried, filtered and concentrated without further work-up(R) -benzyl 2- (1- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) -6-fluoro-5-nitro-1H-indol-2-yl) -2-methylpropionate used directly in the next step, calculated ESI-MS M/z 470.2, experimental 471.5 (M +1)⁺. Retention time 2.20 min methyl 2- (1- (((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) -6-fluoro-5-nitro-1H-indol-2-yl) -2-methylpropionate ((S) -2, 2-dimethyl-1, 3-dioxolan-4-yl) ESI-MS M/z calculated 494.5, Experimental 495.7(M +1)⁺Retention time 2.01 min.

Step 2: (R) -2- (1- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) -6-fluoro-5-nitro-1H-indol-2-yl) -2-methylpropan-1-ol

The crude reaction mixture obtained in step (a) was dissolved in THF (tetrahydrofuran) (42mL) and cooled in an ice-water bath. LiAlH4(16.8mL of a 1M solution, 16.8mmol) was added dropwise, after the addition was complete, the mixture was stirred for an additional 5 minutes. The reaction was quenched by the addition of water (1mL), 15% NaOH solution (1mL), and then water (3 mL). The filtrate was concentrated and purified by column chromatography (30-60% ethyl acetate-hexanes) to give (R) -2- (1- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) -6-fluoro-5-nitro-1H-indol-2-yl) -2-methylpropan-1-ol as a brown oil (2.68g, 87% over 2 steps.) ESI-MS M/z calcd for 366.4, experimental 367.3 (M +1)⁺. Retention time 1.68 minutes.¹H NMR (400MHz, DMSO-d6)8.34(d, J ═ 7.6Hz, 1H), 7.65(d, J ═ 13.4Hz, 1H), 6.57(s, 1H), 4.94(t, J ═ 5.4Hz, 1H), 4.64-4.60(m, 1H), 4.52-4.42(m, 2H), 4.16-4.14(m, 1H), 3.76-3.74(m, 1H), 3.63-3.53(m, 2H), 1.42(s, 3H), 1.38-1.36(m, 6H) and 1.19(s, 3H) ppm. (DMSO is dimethylformamide).

And step 3: (R) -2- (5-amino-1- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) -6-fluoro-1H-indol-2-yl) -2-methylpropan-1-ol

(R) -2- (1- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) -6-fluoro-5-nitro-1H-indol-2-yl) -2-methylpropan-1-ol (2.5g, 6.82mmol) was dissolved in ethanol (70mL) and washed with N2 rinse reactant, then add Pd-C (250mg, 5 wt.%)₂(atm) stirring. After 2.5 hours, only partial conversion to product was observed by LCMS the reaction was filtered through celite and concentrated the residue was again subjected to the above conditions after 2 hours LCMS indicated complete conversion to product. The reaction mixture was filtered through celite the filtrate was concentrated to give the product (1.82g, 79%). ESI-MS calculated M/z 336.2, Experimental 337.5(M +1)⁺. Retention time 0.86 minutes.¹H NMR (400MHz, DMSO-d6)7.17(d, J ═ 12.6Hz, 1H), 6.76(d, J ═ 9.0Hz, 1H), 6.03(s, 1H), 4.79-4.76 (m, 1H), 4.46(s, 2H), 4.37-4.31(m, 3H), 4.06(dd, J ═ 6.1, 8.3Hz, 1H), 3.70-3.67 (m, 1H), 3.55-3.52(m, 2H), 1.41(s, 3H), 1.32(s, 6H) and 1.21(s, 3H) ppm.

And 4, step 4: (R) -1- (2, 2-difluorobenzo [ d ] [1, 3] dioxol-5-yl) -N- (1- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) -6-fluoro-2- (1-hydroxy-2-methylpropan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide

DMF (3 drops) was added to 1- (2, 2-difluorobenzo [ d ]][1，3]Dioxol-5-yl) cyclopropanecarboxylic acid (1.87g, 7.7mmol) and thionyl chloride (1.30mL, 17.9mmol) in a stirred mixture after 1 hour a clear solution had formed the solution was concentrated in vacuo, followed by addition of toluene (3mL) and concentration of the mixture again the toluene step was repeated again and the residue was placed under high vacuum for 10 minutes. The acid chloride was then dissolved in dichloromethane (10mL) and added to a mixture of (R) -2- (5-amino-1- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) -6-fluoro-1H-indol-2-yl) -2-methylpropan-1-ol (1.8g, 5.4mmol) and triethylamine (2.24mL, 16.1mmol) in dichloromethane (45 mL). The reaction was stirred at room temperature for 1 hour. The reaction was washed with 1N HCl solution, NaHCO₃The saturated solution and brine were washed over MgSO₄Drying and concentration gave the product (3g, 100%). ESI-MS M/z calculated 560.6, Experimental 561.7(M +1)⁺. Retention time 2.05 min. ¹H NMR(400MHz，DMSO-d6)8.31(s，1H)，7.53(s，1H)，7.42-7.40(m，2H)，7.34 -7.30(m，3H)，6.24(s，1H)，4.51-4.48(m1H), 4.39-4.34(m, 2H), 4.08(dd, J ═ 6.0, 8.3Hz, 1H), 3.69(t, J ═ 7.6Hz, 1H), 3.58-3.51(m, 2H), 1.48-1.45(m, 2H), 1.39(s, 3H), 1.34-1.33(m, 6H), 1.18(s, 3H) and 1.14-1.12(m, 2H) ppm.

And 5: (R) -1- (2, 2-difluorobenzo [ d ] [1, 3] dioxol-5-yl) -N- (1- (2, 3-dihydroxypropyl) -6-fluoro-2- (1-hydroxy-2-methylpropan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide

Reacting (R) -1- (2, 2-difluorobenzo [ d ]][1，3]Dioxolen-5-yl) -N- (1- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) -6-fluoro-2- (1-hydroxy-2-methylpropan-2-yl) -1H-indol-5-yl) cyclopropanecarboxamide (3.0g, 5.4mmol) was dissolved in methanol (52mL) Water (5.2mL) was added followed by p-TsOH₂O (p-toluenesulfonic acid hydrate) (204mg, 1.1 mmol.) the reaction was heated at 80 ℃ for 45 minutes the solution was concentrated and then partitioned between ethyl acetate and NaHCO₃Between saturated solutions. The ethyl acetate layer was then washed with MgSO₄Drying and concentration the residue was purified by column chromatography (50-100% ethyl acetate-hexanes) to give the product (1.3 g, 47%, ee > 98% by SFC.) calculated ESI-MS M/z 520.5, experimental 521.7(M +1)⁺Retention time 1.69 minutes. ¹H NMR (400MHz, DMSO-d6)8.31(s, 1H), 7.53(s, 1H), 7.42-7.38(m, 2H), 7.33-7.30(m, 2H), 6.22(s, 1H), 5.01(d, J ═ 5.2Hz, 1H), 4.90(t, J ═ 5.5Hz, 1H), 4.75(t, J ═ 5.8Hz, 1H), 4.40(dd, J ═ 2.6, 15.1Hz, 1H), 4.10(dd, J ═ 8.7, 15.1Hz, 1H), 3.90(s, 1H), 3.65-3.54(m, 2H), 3.48-3.33(m, 2H), 1.48-1.45 (m, 2H), 1.35(s, 3H), 1.11 (s, 1H), and 14.11 (m, 1H).

Synthesis of compound III: n- (2, 4-di-tert-butyl-5-hydroxyphenyl) -4-oxo-1, 4-dihydroquinoline-3-carboxamide

Part A: synthesis of 4-oxo-1, 4-dihydroquinoline-3-carboxylic acid

Step 1: 2-Phenylaminomethylene malonic acid diethyl ester

A mixture of aniline (25.6g, 0.275mol) and diethyl 2- (ethoxymethylene) malonate (62.4g, 0.288mol) was heated at 140 ℃ for 2 h. The mixture was cooled to room temperature and dried under reduced pressure to give 2-phenylaminomethylene-malonic acid diethyl ester as a solid, which was used in the next step without further purification.¹H NMR(DMSO-d6)11.00(d，1H)，8.54(d，J＝13.6Hz，1H)，7.36-7.39(m， 2H)，7.13-7.17(m，3H)，4.17-4.33(m，4H)，1.18-1.40(m，6H)。

Step 2: 4-Hydroxyquinoline-3-carboxylic acid ethyl ester

A 1L three-necked flask equipped with a mechanical stirrer was charged with diethyl 2-phenylaminomethylene-malonate (26.3g, 0.100mol), polyphosphoric acid (270g) and phosphorus oxychloride (750g), the mixture was heated to 70 ℃ and stirred for 4h, the mixture was cooled to room temperature and filtered. The residue was washed with Na ₂CO₃Aqueous work-up, filtration, washing with water and drying 4-hydroxyquinoline-3-carboxylic acid ethyl ester (15.2g, 70%) was obtained as a light brown solid.

And step 3: 4-oxo-1, 4-dihydroquinoline-3-carboxylic acid

4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15g, 69mmol) was suspended in sodium hydroxide solution (2N, 150mL) and stirred at reflux for 2h after cooling, the mixture was filtered and the filtrate was acidified to pH 4 with 2N HCl the resulting precipitate was collected by filtration, washed with water and dried in vacuo to give 4-oxo-1, 4-dihydroquinoline-3-carboxylic acid as an off white solid (10.5g, 92%).¹H NMR(DMSO-d6)15.34(s，1H)， 13.42(s，1H)，8.89(s，1H)，8.28(d，J＝8.0Hz，1H)，7.88(m，1H)，7.81(d，J＝8.4Hz， 1H)，7.60(m，1H).

And part B: synthesis of N- (2, 4-di-tert-butyl-5-hydroxyphenyl) -4-oxo-1, 4-dihydroquinoline-3-carboxamide

Step 1: 2, 4-di-tert-butyl-phenyl carbonate methyl ester

Methyl chloroformate (58mL, 750mmol) was added dropwise to 2, 4-di-tert-butyl-phenol (103.2g, 500mmol), Et, cooled to 0 ℃ in an ice-water bath₃N (139mL, 1000mmol) and DMAP (3.05g, 25mmol) in dichloromethane (400 mL). The mixture was allowed to warm to room temperature while stirring overnight, then filtered through silica gel (about 1L) using 10% ethyl acetate-hexanes (about 4L) as an eluent, and the combined filtrates were concentrated to give 2, 4-di-tert-butyl-phenyl ester methyl carbonate (132g, quant.) as a yellow oil. ¹H NMR(400MHz，DMSO-d6)7.35(d，J＝2.4Hz，1H)，7.29(dd，J＝8.5，2.4Hz， 1H)，7.06(d，J＝8.4Hz，1H)，3.85(s，3H)，1.30(s，9H)，1.29(s，9H)。

Step 2: 2, 4-di-tert-butyl-5-nitro-phenyl methyl carbonate and 2, 4-di-tert-butyl-6-nitro-phenyl methyl carbonate

To a stirred mixture of methyl 2, 4-di-tert-butyl-phenyl carbonate (4.76g, 180mmol) in concentrated sulfuric acid (2mL) cooled in an ice water bath was added a cooled mixture of sulfuric acid (2mL) and nitric acid (2 mL.) the addition was slowly completed so that the reaction temperature did not exceed 50 ℃. the reaction was stirred for 2h while warming to room temperature₄) Concentrated and purified by column chromatography (0-10% ethyl acetate-hexanes) to give a mixture of 2, 4-di-tert-butyl-5-nitro-phenyl methyl carbonate and 2, 4-di-tert-butyl-6-nitro-phenyl methyl carbonate as a pale yellow solid (4.28g) which was used directly in the next step.

And step 3: 2, 4-di-tert-butyl-5-nitro-phenol and 2, 4-di-tert-butyl-6-nitro-phenol

A mixture of 2, 4-di-tert-butyl-5-nitro-phenyl methyl carbonate and 2, 4-di-tert-butyl-6-nitro-phenyl methyl carbonate (4.2g, 14.0mmol) was dissolved in MeOH (65mL), after which KOH (2.0g, 36 mmol) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was then made acidic (pH 2-3) by the addition of concentrated HCl and partitioned between water and diethyl ether the ether layer was dried (MgSO ₄) Concentrated and purified by column chromatography (0-5% ethyl acetate-hexanes) to provide 2, 4-bisTert-butyl-5-nitro-phenol (1.31g, 29% over 2 steps) and 2, 4-di-tert-butyl-6-nitro-phenol. 2, 4-di-tert-butyl-5-nitro-phenol:¹h NMR (400MHz, DMSO-d6)10.14(s, 1H, OH), 7.34(s, 1H), 6.83(s, 1H), 1.36(s, 9H), 1.30(s, 9H), 2, 4-di-tert-butyl-6-nitro-phenol:¹H NMR(400MHz，CDCl3)11.48(s，1H)，7.98(d，J＝ 2.5Hz，1H)，7.66(d，J＝2.4Hz，1H)，1.47(s，9H)，1.34(s，9H).

and 4, step 4: 5-amino-2, 4-di-tert-butyl-phenol

To a refluxing solution of 2, 4-di-tert-butyl-5-nitro-phenol (1.86g, 7.40mmol) and ammonium formate (1.86g) in ethanol (75 mL) was added Pd (5 wt%)/activated carbon (900mg). Celite was washed with methanol and the combined filtrates were concentrated to give 5-amino-2, 4-di-tert-butyl-phenol (1.66g, quantitative) as a grey solid.¹H NMR(400 MHz，DMSO-d₆)8.64(s, 1H, OH), 6.84(s, 1H), 6.08(s, 1H), 4.39(s, 2H, NH2), 1.27(m, 18H); HPLC retention time 2.72min, 10-99% CH₃CN, running for 5 min; ESI-MS 222.4M/z [ M + H ]]⁺.

And 5: n- (5-hydroxy-2, 4-di-tert-butyl-phenyl) -4-oxo-1H-quinoline-3-carboxamide

To a suspension of 4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (35.5g, 188mmol) and HBTU (85.7 g, 226mmol) in DMF (280mL) at ambient temperature was added Et ₃N (63.0mL, 451 mmol). The mixture became homogeneous and was stirred for 10min, after which 5-amino-2, 4-di-tert-butyl-phenol (50.0g, 226mmol) was added in small portions. The mixture was stirred at ambient temperature overnight the mixture became heterogeneous through the course of the reaction and after consumption of all the acid (LC-MS analysis, MH +190, 1.71min) the solvent was removed in vacuo. EtOH (ethanol) was added to the orange solid to produce a slurry. The mixture was stirred on a rotary evaporator (bath temperature 65 ℃) for 15min,the mixture was filtered and the solid obtained was washed with hexane to provide a white solid as EtOH crystals (crystallate). Adding Et₂O (diethyl ether) was added to the solid obtained above until a slurry was formed. The mixture was stirred on a rotary evaporator (bath temperature 25 ℃) for 15min without placing the system under vacuum. This procedure was performed a total of five times. The solid obtained after the fifth precipitation was placed under vacuum overnight to afford N- (5-hydroxy-2, 4-di-tert-butyl-phenyl) -4-oxo-1H-quinoline-3-carboxamide (38g, 52%). HPLC retention time 3.45min, 10-99% CH₃CN, running for 5 min;¹h NMR (400MHz, DMSO-d6)12.88(s, 1H), 11.83 (s, 1H), 9.20(s, 1H), 8.87(s, 1H), 8.33(dd, J ═ 8.2, 1.0Hz, 1H), 7.83-7.79(m, 1H), 7.76(d, J ═ 7.7Hz, 1H), 7.54-7.50(m, 1H), 7.17(s, 1H), 7.10(s, 1H), 1.38(s, 9H), 1.37(s, 9H); ESI-MS calculated m/z 392.21; experimental value 393.3[ M + H ] ]⁺。

Synthesis of compound IV: 3- (6- (1- (2, 2-difluorobenzo [ d ] [1, 3] dioxol-5-yl) cyclopropanecarboxamido) -3-methylpyridin-2-yl) benzoic acid

Compound IV can be prepared according to schemes IV-a to IV-D by coupling an acid chloride moiety with an amine moiety.

Scheme IV-a. synthesis of acid chloride moieties.

Scheme IV-A depicts the preparation of 1- (2, 2-difluorobenzo [ d ] [1, 3] dioxol-5-yl) cyclopropanecarbonyl chloride for preparing the amide bond of Compound IV in scheme IV-C.

Starting material 2, 2-difluorobenzo [ d][1，3]Dioxole-5-carboxylic acid is available from Saltigo (a subsidiary of the Lanxess company). Reacting 2, 2-difluorobenzo [ d ]][1，3]Reduction of the formic acid moiety in dioxole-5-carboxylic acid to the primary alcohol followed by thionyl chloride (SOCl)₂) Conversion to the corresponding chloride affords 5- (chloromethyl) -2, 2-difluoroBenzo [ d ] carbonyl][1，3]Dioxoles which are subsequently converted to 2- (2, 2-difluorobenzo [ d ] using sodium cyanide][1，3]Dioxol-5-yl) acetonitrile treatment of 2- (2, 2-difluorobenzo [ d ] with base and 1-bromo-2-chloroethane][1，3]Dioxol-5-yl) acetonitrile to provide 1- (2, 2-difluorobenzo [ d ]][1，3]Dioxol-5-yl) cyclopropanecarbonitrile 1- (2, 2-difluorobenzo [ d ] using a base ][1，3]Conversion of the nitrile moiety in dioxol-5-yl) cyclopropanecarbonitrile to a carboxylic acid to give 1- (2, 2-difluorobenzo [ d ]][1，3]Dioxol-5-yl) cyclopropanecarboxylic acid, which is converted to the desired acid chloride using thionyl chloride.

Scheme IV-b.

Scheme IV-B depicts an alternative synthesis of the necessary acid chloride 5-bromomethyl-2, 2-difluoro-1, 3-benzodioxole is coupled with ethyl cyanoacetate in the presence of a palladium catalyst to form the corresponding alpha cyanoethyl ester. Saponification of the ester moiety to the carboxylic acid yields cyanoethyl compounds iv. alkylation of cyanoethyl compounds with 1-bromo-2-chloroethane in the presence of a base yields cyanocyclopropyl compounds. Treatment of the cyanocyclopropyl compound with a base produces a carboxylate salt, which is converted to a carboxylic acid by treatment with an acid. The conversion of the carboxylic acid to the acid chloride is then achieved using a chlorinating agent such as thionyl chloride or the like.

Scheme IV-c. synthesis of amine moieties.

Scheme IV-C depicts the preparation of the requisite tert-butyl 3- (6-amino-3-methylpyridin-2-yl) benzoate coupled with 1- (2, 2-difluorobenzo [ d ] [1, 3] dioxol-5-yl) cyclopropanecarbonyl chloride to give compound IV in scheme IV-C. Palladium catalyzed coupling of 2-bromo-3-methylpyridine with 3- (tert-butoxycarbonyl) phenylboronic acid yields tert-butyl 3- (3-methylpyridin-2-yl) benzoate, which is subsequently converted to the desired compound.

Scheme IV-d. acid salts of 3- (6- (1- (2, 2-difluorobenzo [ d ] [1, 3] dioxol-5-yl) cyclopropanecarboxamido) -3-methylpyridin-2-yl) benzoic acid are formed.

Scheme IV-D depicts the coupling of 1- (2, 2-difluorobenzo [ D ] [1, 3] dioxol-5-yl) cyclopropanecarbonyl chloride with tert-butyl 3- (6-amino-3-methylpyridin-2-yl) benzoate using triethylamine and 4-dimethylaminopyridine to first provide the tert-butyl ester of Compound IV.

Synthesis of Compounds

General UPLC/HPLC analytical methods:

unless indicated, the yields of the enantiomers separated by chiral SFC are given as a percentage of the theoretical yield of a single enantiomer of the racemate.

LC method A: analytical reversed phase UPLC, using Acquity UPLC BEH C manufactured by Waters₁₈Column (30X 2.1mm, 1.7 μm particles) (pn: 186002349) and a double gradient run of 1-99% mobile phase B over 1.2 minutes. Mobile phase a ═ water (0.05% trifluoroacetic acid) · mobile phase B ═ acetonitrile (0.035% trifluoroacetic acid) · flow rate 1.5mL/min, injection volume 1.5 μ L, and column temperature 60 ℃.

LC method B: analytical reversed phase UPLC, using Acquity UPLC BEH C manufactured by Waters₁₈Dual gradient runs of column (50 × 2.1mm, 1.7 μm particles) (pn: 186002350) and 1-99% mobile phase B over 3.0 min mobile phase a ═ water (0.05% trifluoroacetic acid),. mobile phase B ═ acetonitrile (0.035% trifluoroacetic acid),. flow rate ═ 1.2mL/min, injection volume ═ 1.5 μ L, and column temperature ═ 60 ℃.

LC method C: analytical reverse phase HPLC using Kinetex C₁₈Column (50 × 3.0mm) and dual gradient run over 6min of 5-100% mobile phase B mobile phase a ═ water (0.1% trifluoroacetic acid), mobile phase B ═ acetonitrile (0.1% trifluoroacetic acid), flow rate ═ 1.5mL/min, injection volume ═ 2 μ L, and column temperature＝30℃.

LC method D: analytical reversed phase UPLC, using Acquity UPLC BEH C manufactured by Waters₁₈Column (50X 2.1mm, 1.7 μm particles) (pn: 186002350) and a double gradient run of 1-99% mobile phase B over 5.0 minutes. Mobile phase a ═ water (0.05% trifluoroacetic acid). Mobile phase B ═ acetonitrile (0.035% trifluoroacetic acid). flow rate ═ 1.2mL/min, injection volume ═ 1.5 μ L, and column temperature ═ 60 ℃.

LC method E: analytical reversed phase UPLC, using Acquity UPLC BEH C manufactured by Waters₁₈Column (50X 2.1mm, 1.7 μm particles) (pn: 186002350) and a double gradient run of 1-99% mobile phase B over 2.5 minutes. Mobile phase a ═ water (0.05% trifluoroacetic acid). Mobile phase B ═ acetonitrile (0.035% trifluoroacetic acid). The flow rate was 1.2mL/min, the injection volume was 1.5 μ L, and the column temperature was 60 ℃.

LC method F: analytical reversed phase UPLC, using Acquity UPLC BEH C manufactured by Waters₁₈Column (50X 2.1mm, 1.7 μm particles) (pn: 186002350) and a double gradient run of 1-99% mobile phase B over 15.0 minutes. Mobile phase a ═ water (0.05% trifluoroacetic acid.) mobile phase B ═ acetonitrile (0.035% trifluoroacetic acid). The flow rate was 1.2mL/min, the injection volume was 1.5 μ L, and the column temperature was 60 ℃.

LC method G: analytical reversed phase UPLC, using Acquity UPLC BEH C manufactured by Waters₁₈Dual gradient runs of column (50 × 2.1mm, 1.7 μm particles) (pn: 186002350) and 30-99% mobile phase B over 3.0 min mobile phase a ═ water (0.05% trifluoroacetic acid),. mobile phase B ═ acetonitrile (0.035% trifluoroacetic acid),. flow rate ═ 1.2mL/min, injection volume ═ 1.5 μ L, and column temperature ═ 60 ℃.

LC method H: kinetex C₁₈4.6 × 50mm 2.6 μm. temperature: 45 ℃, flow rate: 2.0mL/min, retention time: and 6 min. Mobile phase: initially, a linear gradient of 95% water (0.1% formic acid) and 5% acetonitrile (0.1% formic acid) to 95% acetonitrile (0.1% formic acid) was continued for 4.0min, followed by holding at 95% acetonitrile (0.1% formic acid) for 2.0min.

LC method I: kinetex C₁₈4.6 × 50mm 2.6 μm. temperature: 45 ℃, flow rate: 2.0mL/min, retention time: 3min. mobile phase: initially, 95% water (0.1% formic acid) and 5% ethylA linear gradient of nitrile (0.1% formic acid) to 95% acetonitrile (0.1% formic acid) was continued for 2.0min, followed by 1.0min at 95% acetonitrile (0.1% formic acid).

LC method J: analytical reversed phase UPLC, using Acquity UPLC BEH C manufactured by Waters₁₈Column (50X 2.1mm, 1.7 μm particles) (pn: 186002350) and a double gradient run of 50-99% mobile phase B over 3.0 minutes. Mobile phase a ═ water (0.05% trifluoroacetic acid.) mobile phase B ═ acetonitrile (0.035% trifluoroacetic acid). The flow rate was 1.2mL/min, the injection volume was 1.5 μ L, and the column temperature was 60 ℃.

LC method K: analytical reversed phase UPLC, using Acquity UPLC BEH C manufactured by Waters₁₈Column (50X 2.1mm, 1.7 μm particles) (pn: 186002350) and a double gradient run of 30-99% mobile phase B over 1.0min. Mobile phase a ═ water (0.05% trifluoroacetic acid). Mobile phase B ═ acetonitrile (0.035% trifluoroacetic acid). The flow rate was 1.2mL/min, the injection volume was 1.5 μ L, and the column temperature was 60 ℃.

LC method L: analytical reversed phase UPLC, using Acquity UPLC BEH C manufactured by Waters₁₈Column (50 × 2.1mm, 1.7 μm particles) (pn: 186002350) and a double gradient run of 50-99% mobile phase B over 1.0min mobile phase a ═ water (0.05% trifluoroacetic acid). Mobile phase B ═ acetonitrile (0.035% trifluoroacetic acid). The flow rate was 1.2mL/min, the injection volume was 1.5 μ L, and the column temperature was 60 ℃.

LC method M: analytical reverse phase HPLC using Kinetex C₁₈Column (50X 3.0mm) and dual gradient run of 5-100% mobile phase B over 6 min. Mobile phase a ═ water (0.1% trifluoroacetic acid). Mobile phase B ═ acetonitrile (0.1% trifluoroacetic acid), flow rate 1.5mL/min, injection volume 10 μ L, and column temperature 30 ℃.

LC method N: zorbax C₁₈4.6X 50mm 3.5 μm. flow rate: 2.0mL/min, gradient (2.0min) of 95% water (0.1% trifluoroacetic acid) + 5% acetonitrile (0.1% trifluoroacetic acid) to 95% acetonitrile (0.1% trifluoroacetic acid), then kept at 95% acetonitrile (0.1% trifluoroacetic acid) for 1.0min.

LC method O: zorbax SB-C₁₈4.6X 50mm 3.5 μm, temperature: 45 ℃, flow 2.0mL/min, run time: mobile phase conditions 4 min: initially, 95% water (0.1% formic acid)) And a linear gradient of 5% acetonitrile (0.1% formic acid) to 95% acetonitrile (0.1% formic acid) for 2.0min, followed by holding at 95% acetonitrile (0.1% formic acid) for 2.0 min.

LC method P: merckmilipore Chromolith speedROD C₁₈Column (50 × 4.6mm) and a double gradient run of 5-100% mobile phase B over 6min mobile phase a ═ water (0.1% trifluoroacetic acid).

LC method Q: merckmilipore Chromolith speedROD C₁₈Column (50X 4.6mm) and dual gradient run of 5-100% mobile phase B over 12 min. Mobile phase a ═ water (0.1% trifluoroacetic acid). Mobile phase B ═ acetonitrile (0.1% trifluoroacetic acid).

LC method R: waters Cortex 2.7. mu. m C₁₈(3.0 mm. times.50 mm), temperature: 55 ℃; flow rate: 1.2 mL/min; mobile phase A: 100% water with 0.1% trifluoroacetic acid. Mobile phase B: 100% acetonitrile containing 0.1% trifluoroacetic acid. Gradient: 5% to 100% B over 4min, 0.5min at 100% B, equilibrating to 5% B over 1.5 min.

LC method S: poroshell 120 EC-C₁₈3.0X 50mm 2.7. mu.M, temperature: 45 ℃, flow rate: 2.0mL/min, run time: and 6 min. Mobile phase conditions: initially, a linear gradient of 95% water (0.1% trifluoroacetic acid) and 5% acetonitrile (0.1% trifluoroacetic acid) was made to 95% acetonitrile (0.1% trifluoroacetic acid) for 4.0min, followed by holding at 95% acetonitrile (0.1% trifluoroacetic acid) for 2.0 min.

LC method T: zorbax C₁₈4.6 × 50mm 3.5 μ M, safety protection: AJO-4287C₁₈4X 3.0 mm. Temperature: 45 ℃, flow rate: 2.0mL/min, run time: and 6 min. Mobile phase: a linear gradient of 95% water (0.1% formic acid) and 5% acetonitrile (0.1% formic acid) to 95% acetonitrile (0.1% formic acid) for 4.0min, followed by 2.0min.

LC method U: kinetex EVO C₁₈4.6X 50mm 2.6 μm, temperature: 45 ℃, flow rate: 2.0mL/min, run time: and 4 min. Mobile phase: initially, a linear gradient of 95% water (0.1% formic acid) and 5% acetonitrile (0.1% formic acid) to 95% acetonitrile (0.1% formic acid) was continued for 2.0min, followed by holding at 95% acetonitrile (0.1% formic acid) for 2.0min.

Practice ofExample 1: preparation of 12, 12, 19-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl-)]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracosane-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (compound 9)

Step 1: 2, 6-dichloropyridine-3-carboxylic acid tert-butyl ester

A solution of 2, 6-dichloropyridine-3-carboxylic acid (10g, 52.08mmol) in tetrahydrofuran (210mL) was treated sequentially with di-tert-butyl dicarbonate (17g, 77.89mmol) and 4- (dimethylamino) pyridine (3.2g, 26.19mmol) and stirred at room temperature overnight at which time 1N (400mL) of hydrochloric acid was added and the mixture stirred vigorously for about 10min, the product was extracted with ethyl acetate (2X 300mL), and the combined organic layers were washed with water (300mL) and brine (150mL) and dried over sodium sulfate, filtered and concentrated under reduced pressure to give 12.94g (96% yield) of tert-butyl 2, 6-dichloropyridine-3-carboxylate as a colorless oil. ¹H NMR(300MHz，CDCl₃) 1.60(s, 9H), 7.30(d, J ═ 7.9Hz, 1H), 8.05(d, J ═ 8.2Hz, 1H), ESI-MS M/z calculated 247.02, experimental 248.1(M +1)⁺(ii) a Retention time: 1.79min (LC method B).

Step 2: 3-oxo-2, 3-dihydro-1H-pyrazole-1-carboxylic acid tert-butyl ester

The 50L reactor was started, and the jacket was set to 20 ℃ with stirring at 150rpm, a reflux condenser (10 ℃) and a nitrogen purge. Methanol (2.860L) and (E) -methyl 3-methoxyprop-2-enoate (2.643kg, 22.76mol) were added and the reactor was capped. Will reactThe contents were heated to an internal temperature of 40 ℃ and the system was set to maintain the jacket temperature at 40 ℃. Hydrazine hydrate (1300g, 55% w/w, 22.31mol) was added portionwise through an addition funnel over 30 min. The reaction mixture was cooled to 20 ℃ and triethylamine (2.483kg, 3.420L, 24.54mol) was added portionwise maintaining the reaction temperature < 30 ℃ a solution of Boc anhydride (4.967kg, 5.228L, 22.76mol) in methanol (2.860L) was added portionwise maintaining the temperature < 45 ℃. The reaction mixture was stirred at 20 ℃ for 16h the reaction solution was partially concentrated to remove methanol, yielding a clear light amber oil. The resulting oil was transferred to a 50L reactor, stirred and water (7.150L) and heptane (7.150L) were added, the addition caused a small amount of product to precipitate, the aqueous layer was drained into a clean vessel and the interface and heptane layers were filtered to separate the solid (product). The aqueous layer was transferred back into the reactor and the collected solids were placed back into the reactor and mixed with the aqueous layer. A dropping funnel was added to the reactor and loaded with dropwise addition of acetic acid (1.474kg, 1.396L, 24.54 mol.) the jacket was set to 0 ℃ to absorb the quench exotherm. After complete addition (pH 5), the reaction mixture was stirred for 1 h. The solid was collected by filtration and washed with water (7.150L), followed by a second wash with water (3.575L.) the crystalline solid was transferred to a 20L rotary evaporation bulb and heptane (7.150L) was added. The mixture was slurried at 45 ℃ for 30min and 1 to 2 volumes of solvent were distilled off. The slurry in the rotary evaporation flask was filtered and the solid washed with heptane (3.575L.) the solid was further dried in vacuo (50 ℃, 15 mbar) to give tert-butyl 5-oxo-1H-pyrazole-2-carboxylate as a crude crystalline solid (2921g, 71%). ¹H NMR (400MHz, dimethyl sulfoxide-d 6) 10.95(s, 1H), 7.98(d, J ═ 2.9Hz, 1H), 5.90(d, J ═ 2.9Hz, 1H), 1.54(s, 9H).

And step 3: 2-benzylsulfanyl-6-fluoro-pyridines

In a 5L three neck round bottom flask equipped with an overhead stirrer, temperature probe and addition funnel 2,6-Difluoropyridine (200g, 1.738mol) was dissolved in dimethyl sulfoxide (2L). Cesium carbonate (572.4g, 1.757 mol) was added phenyl methanethiol (206mL, 1.755mol) dropwise through an addition funnel, an exotherm was observed during the addition, the temperature was allowed to rise to about 40 ℃, the reaction was stirred at room temperature overnight, the reaction was poured into water and extracted with dichloromethane. The extract was washed twice with water and filtered through a small plug of silica gel the plug was eluted with dichloromethane and the filtrate was evaporated in vacuo to give 2-benzylsulfanyl-6-fluoro-pyridine (366g, 96%) as a peach-colored oil which solidified under vacuum into large pieces.¹H NMR (400MHz, chloroform-d) 7.58 (q, J ═ 7.9Hz, 1H), 7.48-7.41(m, 2H), 7.36-7.25(m, 4H), 7.06(dd, J ═ 7.6, 2.1Hz, 1H), 6.62(dd, J ═ 7.9, 2.6Hz, 1H), 4.43(s, 2H).

And 4, step 4: 6-fluoropyridine-2-sulfonamides

2-Benzylsulfanyl-6-fluoro-pyridine (303.2g, 1.383mol) was dissolved in chloroform (2.0L) in a 12L three-necked round bottom flask equipped with an overhead stirrer and a temperature probe. Water (1.5L) was added and the mixture was cooled to 0 ℃ in an ice bath and stirred vigorously. Chlorine gas from a gas-valve bottle was bubbled vigorously into the reaction by a Pasteur pipette inserted through a septum on the third neck of the flask. The reaction was allowed to cool again, after which chlorine gas was added again, the batch continued until the reaction turned yellow-green and remained so after stirring for 30 min. The organic layers were combined, dried over magnesium sulfate, filtered, and evaporated in vacuo to give a light yellow oil the oil was dissolved in dichloromethane (1.5L) and added dropwise to ammonium hydroxide (1.5L, 40% w/v, 17) in a 12L three-neck round bottom flask equipped with an overhead stirrer, temperature probe, and addition funnel. 12 mol.) ammonium hydroxide solution was cooled to 0 ℃ in an ice bath before addition, the addition rate was adjusted so that the temperature of the reaction was kept below 10 ℃, the resulting yellow-green solution was stirred for one hour and poured into ice, the layers were separated (the organic layer was dark green) and the aqueous layer was extracted again with dichloromethane, the organic layer was discarded, the aqueous layer was cooled in an ice bath and concentrated aqueous hydrochloric acid solution was added portion by portion to the aqueous layer until the pH was strongly acidic. The organic layers were combined, dried over magnesium sulfate, filtered and evaporated in vacuo to give a light brown solid. The resulting mixture was stirred briefly and then filtered. The filter cake was washed with pentane and dried in vacuo to give 6-fluoropyridine-2-sulfonamide as a light brown solid (204.1g, 84%).¹H NMR (300MHz, dimethylsulfoxide-d)₆)8.52-8.11 (m，1H)，7.89(dd，J＝7.8，2.7Hz，1H)，7.67(s，2H)，7.57-7.44(m，1H)。

And 5: 2- [1- (trifluoromethyl) cyclopropyl ] ethanol

To a solution of lithium aluminum hydride (293mg, 7.732mmol) in tetrahydrofuran (10.00mL) in an ice bath was added 2- [1- (trifluoromethyl) cyclopropyl ] acetic acid (1.002g, 5.948 mmol) in tetrahydrofuran (3.0mL) dropwise over a period of 30min, maintaining the reaction temperature below 20 ℃ the mixture was gradually warmed to ambient temperature and stirred for 18 h. The mixture was cooled with an ice bath and quenched sequentially with water (294mg, 295 μ L, 16.36 mmol), sodium hydroxide (297 μ L, 6M, 1.784mmol), and then water (884.0 μ L, 49.07mmol) to give a particulate solid in the mixture. The solid was filtered off using celite and the precipitate was washed with ether. The filtrate was further dried over magnesium sulfate and filtered, and concentrated in vacuo to give a product containing residual tetrahydrofuran and ether. The mixture was used directly in the next step without further purification.

Step 6: 3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazole-1-carboxylic acid tert-butyl ester

5-oxo-1H-pyrazole-2-carboxylic acid tert-butyl ester (1.043g, 5.660mmol) and 2- [1- (trifluoromethyl) cyclopropyl]Ethanol (916mg, 5.943mmol) and triphenylphosphine (1.637g, 6.243mmol) were combined in tetrahydrofuran (10.48mL) and the reaction was cooled in an ice bath diisopropyl azodicarboxylate (1.288g, 1.254 mL, 6.368mmol) was added dropwise to the reaction mixture and the reaction was allowed to warm to room temperature for 16h the mixture was evaporated and the resulting material was partitioned between ethyl acetate (30mL) and 1N sodium hydroxide (30mL) the organic layer was separated, washed with brine (30mL), dried over sodium sulfate and concentrated the crude material was purified by silica gel chromatography eluting with a gradient of ethyl acetate/hexane (0-30%) to give 3- [2- [1- (trifluoromethyl) cyclopropyl ] mass]Ethoxy radical]Pyrazole-1-carboxylic acid tert-butyl ester (1.03g, 57%). ESI-MS M/z calculated 320.13, Experimental 321.1(M +1)⁺(ii) a Retention time: 0.72min (LC method A).

And 7: 3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] -1H-pyrazole

Tert-butyl-3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazole-1-carboxylate (1.03g, 3.216 mmol) was dissolved in dichloromethane (10.30mL) and trifluoroacetic acid (2.478mL, 32.16mmol) and the reaction was stirred at room temperature for 2h the reaction was evaporated and the resulting oil was partitioned between ethyl acetate (10mL) and a saturated solution of sodium bicarbonate the organic layer was separated, washed with brine, dried over sodium sulfate and evaporated to give 3- [2- [1- (trifluoromethyl) cyclopropyl ] methyl ester ]Ethoxy radical]-1H-pyrazole (612mg, 86%).¹H NMR (400 MHz, dimethylsulfoxide-d)₆)11.86(s，1H)，7.50(t，J＝2.1Hz，1H)，5.63(t，J＝2.3Hz, 1H), 4.14(t, J ═ 7.1Hz, 2H), 2.01(t, J ═ 7.1Hz, 2H), 0.96-0.88(m, 2H), 0.88-0.81(m, 2H). ESI-MS M/z calculated 220.08, Experimental 221.0(M +1)⁺(ii) a Retention time: 0.5min (LC method A).

And 8: 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxylic acid tert-butyl ester

2, 6-dichloropyridine-3-carboxylic acid tert-butyl ester (687mg, 2.770mmol), 3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]-1H-pyrazole (610mg, 2.770mmol) and freshly ground potassium carbonate (459mg, 3.324 mmol) in dry dimethyl sulfoxide (13.75 mL.) 1, 4-diazabicyclo [2.2.2 ] was added]Octane (62mg, 0.5540mmol) and the mixture stirred at room temperature under nitrogen for 16 h. The reaction mixture was diluted with water (20mL) and stirred for 15min, the resulting solid was collected and washed with water, the solid was dissolved in dichloromethane and dried over magnesium sulfate, the mixture was filtered and concentrated to give 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] 2-chloro-6- [3- [1- (trifluoromethyl)]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (1.01g, 84%). ESI-MS M/z calculated 431.12, Experimental value 432.1(M +1)⁺(ii) a Retention time: 0.88min (LC method A).

And step 9: 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxylic acid

2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (1.01g, 2.339mmol) and trifluoroacetic acid (1.8mL, 23.39mmol) were combined in dichloromethane (10mL) and heated at 40 ℃ for 3 h. Concentrate the reaction, add hexanes, and concentrate the mixture again to give 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (873mg, 99%). ESI-MS M/z calculated 375.06, experimental 376.1(M +1)⁺(ii) a Retention time: 0.69min (LC method A).

Step 10: 2, 2-dimethyl-5-oxopyrrolidine-1-carboxylic acid tert-butyl ester

5, 5-Dimethylpyrrolidin-2-one (4.77g, 42.1mmol), 4-N, N-dimethylaminopyridine (9.19g, 42.1mmol) and triethylamine (4.26g, 42.1mmol) were dissolved in anhydrous dichloromethane (140mL), followed by dissolution of di-tert-butyl dicarbonate (27.6g, 0.126mol) therein, and the reaction mixture was stirred at room temperature for 48 h. The reaction solution was diluted with dichloromethane (500mL), washed with 1N aqueous hydrogen chloride (100mL) and brine (2X 50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated the residue obtained was chromatographed on silica gel using a hexane-ethyl acetate gradient (0-20% ethyl acetate/hexane) to give tert-butyl 2, 2-dimethyl-5-oxopyrrolidine-1-carboxylate as a white solid (5.48g, 58%). ¹H NMR(250MHz，CDCl₃) 2.48(t, J ═ 8.0Hz, 2H), 1.85(t, J ═ 8.0Hz, 2H), 1.54(s, 9H), 1.47(s, 6H), ESI-MS M/z calculated 213.1, experimental 214.1(M +1)⁺Retention time: 2.36min (LC method C).

Step 11: 5-allyl-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

Tert-butyl 2, 2-dimethyl-5-oxopyrrolidine-1-carboxylate (2.72g, 12.8mmol) was dissolved in anhydrous ether (36mL) and anhydrous tetrahydrofuran (36mL) and then cooled to-78 deg.C. diisobutylaluminum hydride (14.1mmol, 14mL, 1.0M in toluene) was added slowly to the above solution and the resulting solution was stirred at-78 deg.C for 4h, then warmed to room temperature and stirred further for 3 h. Subsequently, methanol (40mL) containing p-toluenesulfonic acid monohydrate (18mg) was added, and the resulting solution was stirred for 19 h. Removing all the solvent under reduced pressure, adding saturated aqueous solution of potassium sodium tartrate to the obtained residueSolution (100mL) and stirred for 3 h. The solution was extracted with diethyl ether (3X 150 mL). The combined organic layers were washed with brine (2 × 50mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give intermediate (2.65g) as a pale yellow oil. This intermediate and allyltrimethylsilane (2.34g, 20.5mmol) were dissolved in anhydrous dichloromethane (60mL) and cooled to-78 ℃ followed by slow addition of boron trifluoride diethyl ether (1.72g, 12.1mmol) after complete addition, the reaction solution was stirred at-78 ℃ for 2h and then stirred at room temperature for another 2h followed by addition of 1M aqueous potassium carbonate (25mL) the organic layer was separated and the aqueous layer was extracted with dichloromethane (3 × 60 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure the residue obtained was chromatographed on silica gel using a hexane-ethyl acetate gradient (0-15% ethyl acetate) to give 5-allyl-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a colorless oil (0.92g, 30%). ¹H NMR(250MHz，CDCl₃)5.76(m, 1H), 5.08-5.01(m, 2H), 3.94-3.82(m, 1H), 2.43(m, 1H), 2.13(m, 1H), 2.00(m, 2H), 1, 70(m, 2H), 1.57(s, 9H), 1.41(s, 3H), 1.28(s, 3H). ESI-MS M/z calculated 239.2, Experimental 240.1(M +1)⁺. Retention time: 3.83min (LC method C).

Step 12: 5- (3-hydroxypropyl) -2, 2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 5-allyl-2, 2-dimethylpyrrolidine-1-carboxylate (920mg, 3.85mmol) in anhydrous tetrahydrofuran (38mL) was added 9-BBN (15.38mmol, 30.8mL, 0.5M in tetrahydrofuran) at 0 deg.C the resulting solution was stirred at room temperature for 3h, the reaction solution was cooled to 0 deg.C, aqueous hydrogen peroxide (38.5mmol, 4.4mL, 30% in water) was added followed by sodium hydroxide (19.25mmol, 3.9mL, 20% in water) and subsequently the reaction solution was stirred at room temperature for 1.5 h. Water (50mL) was added and the aqueous solution was extracted with diethyl ether (4X 80 mL.) the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressureThe obtained residue was purified using hexane and ethyl acetate (0 to 35% ethyl acetate/hexane) to give tert-butyl 5- (3-hydroxypropyl) -2, 2-dimethylpyrrolidine-1-carboxylate (834 mg, 84%) as a colorless oil. ¹H NMR (250MHz, dimethylsulfoxide) 4.39(M, 1H), 3.67(M, 1H), 3.37(M, 2H), 1.88-1.49(M, 6H), 1.40(s, 6H), 1.38(s, 3H), 1.31-1.28(M, 2H), 1.24(s, 3H). ESI-MS M/z Calculations 257.2, Experimental 258.1(M +1)⁺. Retention time: 2.79min (LC method C).

Step 13: 2, 2-dimethyl-5- (3-methanesulfonyloxypropyl) pyrrolidine-1-carboxylic acid tert-butyl ester

Tert-butyl 5- (3-hydroxypropyl) -2, 2-dimethylpyrrolidine-1-carboxylate (3.5g, 13.6mmol) and triethylamine (3.8mL, 27.2mmol) were dissolved in 40mL of dichloromethane and cooled in an ice bath. Methanesulfonyl chloride (1.2mL, 15.0mmol) was added dropwise over a 10min period, and the resulting mixture was stirred in an ice bath for 20 min. The mixture was quenched with a saturated solution of sodium bicarbonate (10mL) and the organic layer was washed with water (10mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford tert-butyl 2, 2-dimethyl-5- (3- ((methanesulfonyl) oxy)) propyl) pyrrolidine-1-carboxylate as an orange oil (4.9g, quantitative yield). ESI-MS M/z calculated 335.5, Experimental 336.3(M +1)⁺(ii) a Retention time: 4.24 min (LC method Q).

Step 14: 5- (3-aminopropyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of 5- (3-methanesulfonyloxy-propyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (4.9g, 13.6 mmol) in 1.4-dioxane (70mL) was added 30% aqueous ammonium hydroxide solution (70mL) and the resulting solution was heated in a sealed container at 60 ℃ to heatThe mixture was concentrated in vacuo and extracted with dichloromethane (3 × 100 mL.) the combined organics were concentrated to an oil and purified by column chromatography on silica gel using a 0-15% dichloromethane-methanol gradient to give tert-butyl 5- (3-aminopropyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (2.14g, 61% yield over two steps) as a light colored oil.¹H NMR (500MHz, dimethylsulfoxide) 3.66(d, 1H), 2.85(br s, 2H), 2.58-2.48(M, 2H), 1.85-1.18(M, 22H). ESI-MS M/z calculated 256.4, Experimental 257.4(M +1)⁺(ii) a Retention time: 3.50min (LC method Q).

Step 15: 5- [3- (tert-Butoxycarbonylamino) propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

Tert-butyl 5- (3-aminopropyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (640mg, 2.496 mmol) was dissolved in dichloromethane (6.4mL) under nitrogen and triethylamine (1.01g, 9.981mmol) was added thereto, followed by di-tert-butyl dicarbonate (1.362g, 6.241mmol) and the mixture was stirred at room temperature for 1 h. The reaction was diluted with ether and saturated aqueous ammonium chloride solution and isolated. The aqueous layer was washed twice more with ether, the combined organic phases were dried over sodium sulfate, filtered and concentrated to a light yellow oil which was purified by silica gel chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate to give 5- [3- (tert-butoxycarbonylamino) propyl ] as a clear oil ]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (720mg, 81%). ESI-MS M/z calculated 356.26752, Experimental 357.3(M +1)⁺(ii) a Retention time: 1.73min (LC method B).

Step 16: 5- [3- [ tert-Butoxycarbonylamino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

Reacting 5- [3- (tert-butyloxycarbonyl) groupAmino) propyl group]Tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (720mg, 2.020mmol) was dissolved in N, N-dimethylformamide (14.4 mL). Potassium carbonate (837.5mg, 6.060mmol) was added followed by methyl iodide (860.2mg, 6.060mmol) and the reaction mixture was stirred at room temperature for 16h, potassium carbonate (1.396g, 10.10mmol) was added followed by methyl iodide (860.2mg, 6.060mmol) and the reaction was stirred overnight sodium hydride (404mg, 10.1mmol) was added and stirred for 6h sodium hydride (121mg, 5.04mmol) was added and the reaction was placed in a refrigerator at 4 ℃ for 3 days the reaction was allowed to warm to room temperature, methyl iodide (860.2mg, 6.060mmol) was added and the reaction was stirred at room temperature overnight. The reaction was diluted with dichloromethane and then washed with water (2X 40 mL.) the organic layer was washed twice with brine, followed by saturated aqueous sodium carbonate solution to bring the reaction mixture to a pH of about 12, then the reaction mixture was extracted with dichloromethane (3X 75 mL). The combined organic fractions were dried over sodium sulfate, filtered, and concentrated to a yellow oil the residue was purified by silica gel chromatography using a gentle gradient of 100% dichloromethane to 20% methanol/dichloromethane to isolate the product 5- [3- [ tert-butoxycarbonyl (methyl) amino ]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (695mg, 93%). ESI-MS M/z calculated 370.28317, experimental 371.5(M +1)⁺(ii) a Retention time: 0.83min (LC method A).

And step 17: 3- (5, 5-dimethylpyrrolidin-2-yl) -N-methyl-propan-1-amine (bistrifluoroacetate)

To 5- [3- [ tert-butoxycarbonyl (methyl) amino group at 0 deg.C]Propyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (695mg, 1-876mmol) in a stirred solution in dichloromethane (6.95mL) was added trifluoroacetic acid (2.891mL, 37.52mmol) and the mixture was stirred at room temperature for 5h. volatiles were removed under reduced pressure and then evaporated from ether 3 times to give 3- (5, 5-dimethylpyrrolidin-2-yl) -N-methyl-propan-1-amine (ditrifluoroacetate) (747.3mg, 100%). ESI-MS M/z calculated 170.1783, experimental 171.3(M +1)⁺(ii) a When reservedThe method comprises the following steps: 0.09min (LC method A).

Step 18: 2-chloro-N- [ (6-fluoro-2-pyridyl) sulfonyl ] -6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide

2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (1.14g, 3.03mmol) and carbonyldiimidazole (590mg, 3.639mmol) were combined in tetrahydrofuran (15.3mL) and stirred for 2 h. At this time, 6-fluoro-2-pyridinesulfonamide (534mg, 3.03mmol) was added, followed by the addition of 1, 8-diazabicyclo [5.4.0 ] ]Undec-7-ene (907 μ L, 6.07mmol) and the reaction was stirred at room temperature for another 30min. The reaction mixture was slowly cooled to room temperature, followed by placing in an ice-water bath to give a white solid cake, which was filtered and washed with hexane, and the solid was dried under reduced pressure to give 2-chloro-N- [ (6-fluoro-2-pyridyl) sulfonyl group]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (1.48g, 89%). ESI-MS M/z calculated 533.05475, Experimental 543.3 (M +1)⁺(ii) a Retention time: 0.72min (LC method A).

Step 19: 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-2-yl) propyl-methyl-amino ] -2-pyridinyl ] sulfonyl ] -6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide

Reacting 2-chloro-N- [ (6-fluoro-2-pyridyl) sulfonyl group]-6- [3- [2- [1 (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (1.033g, 1.876mmol), 3- (5, 5-dimethylpyrrolidin-2-yl) -N-methyl-propane -1-amine (ditrifluoroacetate) (747.3mg, 1.876mmol), potassium carbonate (1.556g, 11.26mmol), and dimethyl sulfoxide (5mL) were added to the vial, capped and heated to 50 ℃ for 20min heating the reaction to 65 ℃ for 90min cooling the reaction back to 50 ℃ and stirring for 32 h. The reaction was cooled to room temperature and 2-chloro-N- [ (6-fluoro-2-pyridyl) sulfonyl was added]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (300mg, 0.5451mmol) and then warmed back to 50 ℃ and stirred overnight. The reaction was cooled to room temperature and poured into water to give a white precipitate. Concentrated hydrochloric acid was added to bring the pH to 4, then the white solid was filtered off and washed with water, followed by hexane. The solid was dissolved in dichloromethane, dried (magnesium sulfate), filtered and concentrated to a white solid. The solid was purified by silica gel chromatography using a gentle gradient from 100% dichloromethane to 20% methanol/dichloromethane to give 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-2-yl) propyl-methyl-amino ] as a white solid]-2-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (350mg, 27%). ESI-MS M/z calculated 683.2268, Experimental 684.5(M +1) ⁺(ii) a Retention time: 0.63min (LC method A).

Step 20: 12, 12, 19-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracosane-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (compound 9)

2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-2-yl) propyl-methyl-amino]-2-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (350mg, 0.5116 mmol), potassium carbonate (353.5mg, 2.558mmol), cesium fluoride (116.6mg, 28.34. mu.L, 0.7674mmol),

Molecular sieves and dimethylsulfoxide (7.077mL) were combined in a vial, purged with nitrogen, capped, heated to 150 ℃ and stirred for 25 h. Cooled to room temperature and then poured into about 150mL of water. The solid was dissolved in dichloromethane, dried (magnesium sulfate), filtered and concentrated to a tan solid, which was purified by silica gel chromatography using a gentle gradient of 100% dichloromethane to 20% methanol/dichloromethane to give 12, 12, 19-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl-acid ]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracosan-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (compound 9) (259.5mg, 78%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.62(s, 1H), 8.22(d, J ═ 2.8Hz, 1H), 7.97(s, 1H), 7.77(dd, J ═ 8.6, 7.3Hz, 1H), 7.13(d, J ═ 7.2Hz, 1H), 7.04(s, 1H), 6.82(d, J ═ 8.7Hz, 1H), 6.13(d, J ═ 2.8Hz, 1H), 4.32(t, J ═ 7.1Hz, 2H), 2.96(s, 3H), 2.08(t, J ═ 7.0Hz, 2H), 1.69(s, 2H), 1.54(d, J ═ 9.7Hz, 5H), 1.35(s, 3H), 1.23(s, 7H), 0.98-0.95 (s, 2H), 89.84 (M ═ 3H, 5H), 2.83 (M ═ 3H, 5H), 2.8, 3H, 5H, 3H, 1.23 (t, 7H), 7H, 0, 0.95, 3H), 3H, 5H, 3H, 2H, 3H⁺(ii) a Retention time: 2.05min (LC method B).

Example 2: preparation of (15S) -12, 12, 19-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracosane-1 (24), 5(10), 6, 8, 20, 22-hexaen-2, 2, 4-trione (compound 10) and (15R) -12, 12, 19-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [183.1.05, 10.011, 15 [ ]]Tetracosane-1 (24), 5(10), 6, 8, 20, 22-hexaen-2, 2, 4-trione (compound 11)

Step 1: (15S) -12, 12, 19-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracosane-1 (24), 5(10), 6, 8, 20, 22-hexaen-2, 2, 4-trione (compound 10) and (15R) -12, 12, 19-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracosane-1 (24), 5(10), 6, 8, 20, 22-hexaen-2, 2, 4-trione (compound 11)

Rac 12, 12, 19-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl-8) was chromatographed by SFC using ChiralPak AS-H (250 × 21.2mm column, 5 μm particle size) and a mobile phase of 15% methanol/85% carbon dioxide (10mL/min over 8.0min) (injection volume of 500 μ L of 32 mg/mL solution in methanol)]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ] ]The tetracosane-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (compound 9) (221.5mg, 0.3420mmol) was subjected to chiral separation to give (15S) -12, 12, 19-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl-l-y-l) as the first enantiomer to be eluted as a white solid]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracos-1 (24), 5(10), 6, 8, 20, 22-hexaen-2, 2, 4-trione (compound 10) (82.3mg, 74%);¹h NMR (400MHz, dimethylsulfoxide-d)₆) 12.64(s，1H)，8.22(d，J＝2.8Hz，1H)，7.98(d，J＝8.3Hz，1H)，7.77(t，J＝7.9Hz， 1H)，7.12(d，J＝7.2Hz，1H)，7.04(s，1H)，6.82(d，J＝8.6Hz，1H)，6.13(d，J＝2.8 Hz，1H)，4.32(t，J＝7.0Hz，2H)，3.60(s，1H)，2.99(s，1H)，2.96(s，3H)，2.08(t，J＝ 7.1Hz，2H)，196-1.84(M, 1H), 1.69(s, 3H), 1.52(s, 6H), 1.35(s, 3H), 1.02-0.83 (M, 5H), ESI-MS M/z calculated 647.2502, experimental 648.4(M +1)⁺(ii) a Retention time: 2.06min (LC method B), and (15R) -12, 12, 19-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid of the second enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracos-1 (24), 5(10), 6, 8, 20, 22-hexaen-2, 2, 4-trione (compound 11) (81.7mg, 74%);¹h NMR (400MHz, dimethylsulfoxide-d) ₆)12.64(s, 1H), 8.22(d, J ═ 2.8Hz, 1H), 7.98(d, J ═ 8.3Hz, 1H), 7.77(t, J ═ 8.0Hz, 1H), 7.12 (d, J ═ 7.3Hz, 1H), 7.03(s, 1H), 6.81(d, J ═ 8.6Hz, 1H), 6.12(d, J ═ 2.7Hz, 1H), 4.41(s, 1H), 4.32(t, J ═ 7.0Hz, 2H), 3.59(s, 1H), 3.01(s, 1H), 2.96(s, 3H), 2.08(t, J ═ 7.1Hz, 2H), 1.92(d, J ═ 8.7, 1H), 1H (s, 3H), 3.69 (s, 3H), 2.08(t, J ═ 7.1H, 2H), 1.83 (s, 3H), 5M-355 (M, M), calculated values of M, 3.83, 5H, M, 3H, 3.3H, 3H, M, 3H, M, 3⁺(ii) a Retention time: 2.06 min (LC method B).

Example 3: preparation of 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 12)

Step 1: (E) - (2-oxotetrahydropyran-3-ylidene) methanolate (sodium salt)

A5L 3-neck round bottom flask was equipped with a mechanical stirrer, heating mantle, addition funnel, J-Kem temperature probe/controller, and nitrogen inlet/outlet the vessel was charged with sodium hydride (59.91g, 60% w/w, 1.498mol) followed by heptane (1.5L) under a nitrogen atmosphere to provide a gray suspension. Stirring was started and the pot temperature was recorded as 19 ℃ the vessel was then charged with ethanol (3.451g, 74.91mmol) and added via syringe, resulting in gas evolution. The addition funnel was charged with a clear pale yellow solution of tetrahydropyran-2-one (150g, 1.498mol) and ethyl formate (111g, 1.50 mol). The solution was added dropwise over 1h, causing gas evolution and allowing a gradual exotherm to 45 ℃. The resulting thick white suspension was then heated to 65 ℃ for 2h and then allowed to cool to room temperature. The mixture was stirred at room temperature overnight (about 10 h). The reaction mixture was filtered under vacuum through a glass frit Buchner funnel (medium porosity) under a stream of nitrogen. The filter cake was displacement washed with heptane (2X 250mL) and pumped for a few minutes the slightly moist heptane cake was transferred to a glass tray and dried in a vacuum oven at 45 ℃ for 15h to provide a white solid (205g, 1.36mol, 91% yield) as the desired product, i.e. (E) - (2-oxotetrahydropyran-3-ylidene) methanolate (sodium salt).

Step 2: 3-methylenetetrahydropyran-2-one

A5L 3-neck round bottom flask was equipped with a mechanical stirrer, heating mantle, addition funnel, J-Kem temperature probe/controller, and nitrogen inlet/outlet. The vessel was charged with (E) - (2-oxotetrahydropyran-3-ylidene) methanolate (sodium salt) (205g, 1.366mol) and tetrahydrofuran (1640mL) under a nitrogen atmosphere, to thereby provide a white suspension. Stirring was started and the pot temperature was recorded as 19 ℃ then the vessel was charged with paraformaldehyde (136.6g, 4.549 mol), added all at once as a solid the resulting suspension was heated to 63 ℃ and the conditions were maintained for 15h after heating the reaction mixture became slightly gelatinousThe residual aqueous solution was extracted (5X 300 mL). The combined organics were dried over sodium sulfate (500g) and then vacuum filtered through a frit buchner funnel with 20mm celite pad the filter cake was displacement washed with ethyl acetate (250mL) the clear filtrate was concentrated under reduced pressure to provide a clear pale yellow oil (135g) as the desired crude product. The material was purified by flash chromatography on silica gel (liquid loading) eluting with a gradient of 100% hexane to 60% ethyl acetate/hexane over 1h, collecting 450mL fractions. The product was analyzed by silica gel TLC, eluting with 3: 1 hexanes/ethyl acetate and observed under UV the product fractions were combined and concentrated under reduced pressure to provide a clear colorless oil (132g, 1.18mol, 72% yield, containing 16 wt% residual ethyl acetate by NMR) as the desired product, 3-methylenetetrahydropyran-2-one. ¹H NMR (400MHz, dimethylsulfoxide-d)₆)6.18(q，J＝1.9Hz， 1H)，5.60(q，J＝1.9Hz，1H)，4.40-4.26(m，2H)，2.61(ddt，J＝7.0，6.3，2.0Hz，2H)， 1.90-1.75(m，2H).

And step 3: 3- (2-methyl-2-nitro-propyl) tetrahydropyran-2-one

A5000 mL 3-neck round bottom flask was equipped with a mechanical stirrer, a cooling bath as a secondary containment, a J-Kem temperature probe, an addition funnel, and a nitrogen inlet/outlet. The vessel was charged with 2-nitropropane (104.9g, 1.177mol) under a nitrogen atmosphere stirring was started and the pot temperature was recorded as 19 ℃. Subsequently charging the container with 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene (22.41g, 147.2mmol), added in one portion without doping, produced a clear pale yellow solution. The addition funnel was charged with a solution of 3-methylenetetrahydropyran-2-one (110 g, 981.0mmol) in acetonitrile (1100mL), which was added dropwise over 1h, yielding a clear pale yellow solution and allowing gradual exotherm to 24 ℃. The remaining residue was dissolved in dichloromethane (1000mL) and partitioned with 500mL of a 3: 2 mixture of 1 molar citric acid solution/saturated sodium chloride solutionThe combined organics were washed with a saturated solution of sodium chloride (300mL), dried over sodium sulfate (250g) and then filtered through a frit Buchner funnel, the filtrate was concentrated under reduced pressure to a volume of about 200mL, the clear bluish dichloromethane solution was diluted with methyl tert-butyl ether (1500mL), and the cloudy solution was concentrated under reduced pressure to a volume of about 200mL to provide a suspension, the mixture was again diluted with methyl tert-butyl ether (1500mL) and concentrated under reduced pressure to a volume of about 250mL, the resulting suspension was allowed to stand overnight at room temperature (about 12 h). The solid was collected by vacuum filtration in a frit Buchner funnel and the filter cake was displacement washed with low temperature methyl tert-butyl ether (2X 150mL) and then pumped for 30 min. The material was further dried in a vacuum oven at 45 ℃ for 5h to provide a white solid (160g, 0.795mol, 81% yield) as the desired product, i.e., 3- (2-methyl-2-nitro-propyl) tetrahydropyran-2-one. ¹H NMR (400MHz, dimethylsulfoxide-d)₆)4.34(ddd，J ＝11.1，9.3，4.3Hz，1H)，4.20(dt，J＝11.1，5.1Hz，1H)，2.75-2.62(m，1H)，2.56(dd， J＝14.9，5.2Hz，1H)，2.01-1.89(m，2H)，1.89-1.67(m，2H)，1.55(d，J＝6.0Hz， 6H)，1.44(dddd，J＝12.8，11.5，8.1，6.6Hz，1H).

And 4, step 4: 3- (3-hydroxypropyl) -5, 5-dimethyl-pyrrolidin-2-one

A1000 mL 3-neck round bottom flask was equipped with a Teflon stir bar, heating mantle, J-Kem temperature probe/controller, and rubber septum the vessel was charged with 3- (2-methyl-2-nitro-propyl) tetrahydropyran-2-one (25g, 124.2 mmol) and ethanol (375mL) to provide a white suspension. Stirring was started and the suspension was heated to 40 ℃ for 10min, providing a clear colorless solution. The vessel was then fitted with a gas dispersion tube and the solution degassed with nitrogen for 15minAmount, 68.31mmol) and then fitting the vessel with a septum. The process was repeated for three cycles, then the vessel was placed under 1 atmosphere of hydrogen and the reaction mixture was gradually heated to 60 ℃. The reaction was stirred for an additional 24h at 60 ℃. After cooling to room temperature, the vessel was equipped with a gas dispersion tube and the reaction mixture was degassed with nitrogen for 15min, the mixture was vacuum filtered through a glass frit buchner funnel with a 20mm celite layer, the filter cake was displacement washed with ethanol (2 x 100mL) and pumped until the ethanol was slightly wet, then wetted with water and the used raney nickel catalyst was discarded in water. The clear light amber filtrate was concentrated under reduced pressure to a clear viscous light amber oil the oil was diluted with methyl tert-butyl ether (1500mL) and the cloudy solution was concentrated under reduced pressure to a volume of about 150mL to provide a suspension the mixture was again diluted with methyl tert-butyl ether (1500mL) and concentrated under reduced pressure to a volume of about 150 mL. The resulting suspension was allowed to stand overnight at room temperature (about 12 h). The solid was collected by vacuum filtration in a frit Buchner funnel and the filter cake was displacement washed with low temperature methyl tert-butyl ether (2X 50mL) and then pumped for 30 min. The material was further dried in a vacuum oven at 45 ℃ for 3h to provide a white solid (19g, 0.111 mol, 89% yield) as the product, i.e. 3- (3-hydroxypropyl) -5, 5-dimethyl-pyrrolidin-2-one. ¹H NMR (400 MHz, dimethylsulfoxide-d)₆)7.63(s，1H)，3.38(t，J＝6.5Hz，2H)，2.37(tdd，J＝9.8，8.5，4.4 Hz，1H)，2.02(dd，J＝12.3，8.6Hz，1H)，1.72(tdd，J＝9.6，7.5，4.4Hz，1H)，1.52- 1.32(m，3H)，1.28-1.03(m，7H).

And 5: 3- (5, 5-dimethylpyrrolidin-3-yl) propan-1-ol

A5L 3-neck round bottom flask was equipped with a mechanical stirrer, heating mantle, addition funnel, J-Kem temperature probe/controller and nitrogen inlet/outlet the vessel was charged with lithium aluminum hydride pellets (19.39g, 510.9mmol) under a nitrogen atmosphere. Subsequently charging the container with tetrahydroFuran (500mL, 20 mL/g). Stirring was started and the pot temperature was recorded as 20 ℃. The mixture was stirred at room temperature for 0.5h to dissolve the pellets. The pot temperature of the resulting grey suspension was recorded as 24 ℃. The addition funnel was charged with a solution of 3- (3-hydroxypropyl) -5, 5-dimethyl-pyrrolidin-2-one (25g, 146.0mmol) in tetrahydrofuran (500mL) and the clear pale yellow solution was added dropwise over 90 min. At this point, analysis of the reaction mixture indicated that some residual starting material remained and no change in product formation. Then, the reaction was stopped at this time. The heating jacket was removed and the vessel was fitted with a cooling bath. The suspension was cooled to 0 ℃ with a crushed ice/water cooling bath and then quenched by very slow dropwise addition of water (19.93mL), followed by addition of 15 wt% sodium hydroxide solution (19.93mL) and then at the end with water (59.79 mL). The pot temperature of the resulting white suspension was recorded as 5 ℃. The cooling bath was removed and the vessel was again fitted with a heating jacket. The suspension was warmed to 60 ℃ and the conditions were maintained for 30min. The warm suspension was filtered under vacuum through a glass frit Buchner funnel with 20mm celite pad then the filter cake was displacement washed with 60 ℃ tetrahydrofuran (2X 250mL) and then pumped for 30min the clear filtrate was concentrated under reduced pressure to give a clear pale yellow viscous oil (23.5g, 0.149mol, 99% yield) as the desired product, i.e. 3- (5, 5-dimethylpyrrolidin-3-yl) propan-1-ol. ¹H NMR (400 MHz, dimethylsulfoxide-d)₆)3.37(dt，J＝8.3，6.4Hz，3H)，2.95(dd，J＝10.6，7.6Hz，1H)， 2.40(dd，J＝10.7，7.7Hz，1H)，2.04(dt，J＝16.1，8.1Hz，1H)，1.69(dd，J＝12.2，8.2 Hz，1H)，1.50-1.24(m，5H)，1.11-0.94(m，7H).

Step 6: 4- (3-hydroxypropyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

A1L 3-necked round bottom flask was equipped with a mechanical stirrer, cooling bath, additionFunnel, J-Kem temperature probe and nitrogen inlet/outlet the vessel was charged with 3- (5, 5-dimethylpyrrolidin-3-yl) propan-1-ol (15g, 95.39mmol) and dichloromethane (225mL, 15mL/g) under a nitrogen atmosphere to provide a clear light yellow solution. Stirring was started and the pot temperature was recorded as 19 ℃. The cooling bath was charged with crushed ice/water and the pot temperature was lowered to 0 ℃. Triethylamine (12.55g, 124.0mmol) was charged to the addition funnel, which was then added drop wise over 5min without doping. No exotherm was observed the addition funnel was then charged with di-tert-butyl dicarbonate (22.89g, 104.9mmol) dissolved in dichloromethane (225 mL). The clear pale yellow solution was then added dropwise over 30min, resulting in slight gas evolution, no exotherm was observed, the cooling bath was removed, and the resulting clear pale yellow solution was allowed to warm to room temperature and stirring continued at room temperature for 3 h. The reaction mixture was transferred to a separatory funnel and partitioned with water (75 mL.) the organics were removed and washed with a saturated solution of sodium chloride (75mL), dried over sodium sulfate (150g) and then filtered through a glass frit buchner funnel. The filtrate was concentrated under reduced pressure to provide a clear pale yellow oil (30g) as the desired crude material this material was purified by flash chromatography on silica gel column (liquid load with dichloromethane) eluting with a gradient of 100% dichloromethane to 10% methanol/dichloromethane over 60min, collecting 50mL fractions. ¹H NMR(400 MHz，DMSO-d₆)4.38(td，J＝5.2，1.4Hz，1H)，3.54(dt，J＝10.3，6.7Hz，1H)，3.38 (td，J＝6.6，3.5Hz，2H)，2.76(q，J＝10.3Hz，1H)，2.07(td，J＝11.6，5.7Hz，1H)， 1.87(ddd，J＝16.7，12.1，6.0Hz，1H)，1.37(dd，J＝14.2，10.4Hz，17H)，1.24(s，3H)。

And 7: 2, 2-dimethyl-4- (3-methanesulfonyloxypropyl) pyrrolidine-1-carboxylic acid tert-butyl ester

Mixing 4- (3-hydroxypropyl) -2, 2-diMethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (50.5g, 196.22mmol) and triethylamine (39.711g, 54.698mL, 392.44mmol) were dissolved in dichloromethane (500mL) and the resulting solution was cooled in an ice-water bath for 30min, methanesulfonyl chloride (24.725g, 16.706 mL, 215.84mmol) was added dropwise over a period of 30min, the ice bath was then removed, and the mixture was stirred at room temperature for one hour then quenched with a saturated solution of sodium bicarbonate (200 mL). The phases were separated and the organic phase was extracted with saturated sodium bicarbonate (200mL) and water (2 × 100mL) the aqueous phase was discarded and the organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford tert-butyl 2, 2-dimethyl-4- (3-methanesulfonyloxypropyl) pyrrolidine-1-carboxylate (64.2g, 93%) as a pale yellow oil. ESI-MS M/z calculated 335.1766, Experimental 336.4(M +1)⁺(ii) a Retention time: 5.54min (LC method Q).

And 8: 4- (3-aminopropyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

Tert-butyl 2, 2-dimethyl-4- (3-methanesulfonyloxypropyl) pyrrolidine-1-carboxylate (64.2g, 191.38 mmol) was dissolved in dioxane (650mL) and ammonium hydroxide (650mL) was then added and the resulting mixture was heated to 45 ℃ for 18 h. After 18h, the reaction was cooled to room temperature. Dilute the solution with 1M sodium hydroxide (200mL) and then extract with diethyl ether (3 x 650 mL.) discard the aqueous phase and extract the combined organic phase with water (2 x 200 mL.) discard the aqueous phase and dry the organic phase over sodium sulfate, filter and concentrate in vacuo to give tert-butyl 4- (3-aminopropyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (48.9g, 95%) as a pale yellow oil, calculated ESI-MS M/z 256.2151, experimental 257.3(M +1) ⁺(ii) a Retention time: 3.70min (LC method Q).

And step 9: 2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino ] propyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

To dimethyl sulfoxide (75mL) containing tert-butyl 4- (3-aminopropyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (8.91g, 34.8mmol) and 6-fluoropyridine-2-sulfonamide (6.13g, 34.8mmol) was added potassium carbonate (4.91g, 35.5mmol) and the mixture was stirred at 100 ℃ for 12h and then allowed to cool to ambient temperature and stirred for an additional 4h (total 16 h.) the reaction mixture was poured slowly into water (200mL) containing hydrochloric acid (35mL, 1M, 35.00mmol) (a portion was bubbled) and diluted with ethyl acetate (250 mL.) the organic phase was separated and washed with 100mL brine Purifying the impure fraction by silica gel chromatography eluting with 0% to 100% ethyl acetate/hexane to obtain all 2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (10.0g, 69%). ¹H NMR (400MHz, dimethylsulfoxide-d)₆) 7.52(dd, J ═ 8.5, 7.2Hz, 1H), 7.07(s, 2H), 6.95(dd, J ═ 7.2, 0.7Hz, 2H), 6.61(d, J ═ 8.5Hz, 1H), 3.55(q, J ═ 9.1Hz, 1H), 3.32-3.24(m, 2H), 2.79(q, J ═ 10.0Hz, 1H), 2.13(d, J ═ 16.1Hz, 1H), 1.96-1.82(m, 1H), 1.51(dt, J ═ 18.0, 9.3Hz, 2H), 1.37 (dd, J ═ 12.9, 10.6Hz, 15H), 1.24(s, 3H). ESI-MS M/z calculated 412.21442, Experimental 413.1(M +1)⁺(ii) a Retention time: 2.34min (LC method D).

Step 10: 4- [3- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

Part A: to 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxylic acid (11.4g, 30.34mmol) in tetrahydrofuran (150mL) was slowly added carbonyldiimidazole (5.9g, 36 mmol). The mixture was stirred at ambient temperature for 1 hour. Carbonyl diimidazole (0.5g, 3mmol) was added and the reaction stirred at ambient temperature for an additional 1h (total 2 h).

And part B: addition of 2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino group-containing active ester prepared in part A ]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (10.0g, 24.24mmol) in tetrahydrofuran (50mL) followed by the addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (7.5mL, 50mmol) and the mixture stirred at ambient temperature for 16 h water (200mL) containing citric acid (25.1g, 130.6mmol) was slowly added to the reaction mixture and acidified to about pH 3 the mixture became cloudy but no precipitate formed. The mixture was extracted with ethyl acetate (400mL) and the organic phase was washed with brine, dried over magnesium sulfate, filtered through celite and concentrated in vacuo. Purifying the crude product by silica gel chromatography, eluting with 0-80% ethyl acetate/hexane, to give the product as a foam, i.e. 4- [3- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] propane]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (13.82g, 74%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.79(s, 1H), 8.40(t, J ═ 2.7 Hz, 1H), 8.11(d, J ═ 8.4Hz, 1H), 7.71(d, J ═ 8.3Hz, 1H), 7.62(dd, J ═ 8.5, 7.2Hz, 1H), 7.21(d, J ═ 5.8Hz, 1H), 7.17(d, J ═ 7.1Hz, 1H), 6.74(d, J ═ 8.5Hz, 1H), 6.19 (t, J ═ 2.3Hz, 1H), 4.34(t, J ═ 7.1Hz, 2H), 3.50(dt, J ═ 18.3, 9.0Hz, 1H), 3.23(d, J ═ 6.7, 2H), 2.69 (t, 2.0H), 2.15.15.15H, 15H, 15.7H, 15H, 15.0 (d, 1H), 2.9.0 (d, 1H, 4.9.5H, 15 (d, 15, 2H), 2H) 0.89(d, J ═ 5.0Hz, 2H). ESI-MS M/z calculated 769.2636, Experimental 770.1(M +1) ⁺(ii) a Retention time: 3.48min (LC method D).

Step 11: 2-chloro- { N } - [ [6- [3- (5, 5-dimethylpyrrolidin-3-yl) propylamino ] -2-pyridyl ] sulfonyl ] -6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide (dihydrochloride)

To a solution containing 4- [3- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] amino acid]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (13.8g, 17.92mmol) in dichloromethane (75mL) hydrochloric acid (15mL, 4M, 60.00mmol) was added and the mixture was stirred at ambient temperature for 16 h. The solvent was removed in vacuo and the residue diluted with 100mL ethyl acetate the solvent was removed in vacuo and the dilution was repeated with 100mL ethyl acetate to give a foam, i.e., 2-chloro- { N } - [ [6- [3- (5, 5-dimethylpyrrolidin-3-yl) propylamino]-2-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (dihydrochloride) (13.5g, 101%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.83(s, 1H), 9.06(s, 1H), 8.92(s, 1H), 8.42(d, J-2.8 Hz, 1H), 8.11(d, J-8.4 Hz, 1H), 7.72(d, J-8.4 Hz, 1H), 7.63(dd, J-8.5, 7.2 Hz, 1H), 7.29(s, 1H), 7.18(dd, J-7.2, 0.7Hz, 1H), 6.76(dd, J-8.5, 0.7Hz, 1H), 6.21(d, J-2.9 Hz, 1H), 4.95(s, 2H), 4.35(t, J-7.0 Hz, 2H), 3.41-3.28(m, 3.24(p, 1H), 6.35 (t, J-7.0 Hz, 2H), 3.9H), 6.9H, 1H, 7.9H), 7.35 (s, 2H), 7.7.9H), 7.7.7H, 3.9 (d, 3.9H), 3.9H, 7H, 1H, 7H, 1H, 7, 3.9 (d, 3.9, 3, 7, 3, 7, 5H) 1.24(s, 3H), 1.01-0.93(M, 2H), 0.90(dd, J ═ 7.9, 3.2Hz, 2H) ESI-MS M/z calcd for 669.2112, experimental value 670.0(M +1) ⁺(ii) a Retention time: 2.26min (LC method D).

Step 12: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 12)

To a solution containing 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-3-yl) propylamino group]-2-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (dihydrochloride) (12.9g, 17.36mmol) in NMP (120mL) was added potassium carbonate (9.64g, 69.8mmol) followed by cesium fluoride (2.69g, 17.7mmol) and the slurry was stirred at 150 ℃ for 16 h. The reaction was then allowed to cool to ambient temperature. The mixture was diluted with water (100mL) and poured into water (400mL) and the mixture was slowly acidified with hydrochloric acid (27.0 mL, 6M, 162.0 mmol.) the precipitate was collected using a medium pore glass frit and washed 3 times with 50mL water. The solid was air dried for 1h and then dissolved in ethyl acetate (400mL) the organic phase was concentrated in vacuo and the crude product was purified by silica gel chromatography, eluting with 0-100% ethyl acetate/hexanes. The impure fraction was purified by silica gel chromatography eluting with 0-5% methanol in dichloromethane to provide good separation of the product from impurities. The pure product fractions were combined to give 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] amino acid ]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 12) (7.4g, 67%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.52(s, 1H), 8.22(d, J ═ 2.8Hz, 1H), 7.82(d, J ═ 8.2Hz, 1H), 7.58(dd, J ═ 8.5, 7.2Hz, 1H), 7.05(d, J ═ 7.0Hz, 1H), 7.00(s, 1H), 6.92(d, J ═ 8.2Hz, 1H), 6.71(d, J ═ 8.2Hz, 1H), 6.11(d, J ═ 2.8Hz, 1H), 4.31(t, J ═ 7.0Hz, 2H), 4.02-3.81(m, 1H), 3.15(dt, J ═ 10.1, 3.8Hz, 1H), 2.95(d, J ═ 13.7, 1H, 2.81 (m, 1H), 1.7, 1H), 1.7.78 (d, 1H), 1H), 6.7.51, 1H, 6.7.7, 6.7, 1H, 6.7, 1H, 6.7, 1H, 6.1H, 6.7, 1H, 6.1H, 1H) 0.99-0.93(M, 2H), 0.90(d, J ═ 10.8Hz, 2H), ESI-MS M/z calculated 633.2345, experimental 634.2(M +1)⁺(ii) a Retention time: 2.23min (LC method E).

Example 4: preparation of (14R) -12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 13) and (14S) -12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 14)

Step 1: (14R) -12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 13) and (14S) -12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 14)

Racemic 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (7.4g) was dissolved in 150mL acetonitrile and chiral SFC purification was performed. The sample was separated by chiral SFC chromatography using a ChiralPak AS-H (250X 21.2mm column, 5 μm particle size) and a mobile phase of 25% acetonitrile: methanol (90: 10)/75% carbon dioxide (70mL/min) to give (14R) -12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 13) (2.91 g, 53%);¹h NMR (400MHz, dimethylsulfoxide-d)₆)12.51(s, 1H), 8.21(d, J ═ 2.7Hz, 1H), 7.82(d, J ═ 8.2Hz, 1H), 7.58(t, J ═ 7.8Hz, 1H), 7.05(d, J ═ 7.0Hz, 1H), 6.99(d, J ═ 5.8Hz, 1H), 6.92(d, J ═ 8.2Hz, 1H), 6.71(d, J ═ 8.5Hz, 1H), 6.11(d, J ═ 2.7Hz, 1H), 4.31(t, J ═ 7.0Hz, 2H), 3.93(s, 1H), 3.16(s, 1H), 2.95(d, J ═ 12.7Hz, 1H), 2.80-2.64(m, 1H), 10.81 (t, 10.7H), 1H), 3.6.71 (d, J ═ 5H, 1H), 1H, 4.95 (d, J ═ 12.7Hz, 1H), 1H, 2.81 (d, 1H), 1H, 5H, 1H, 5H, 1, 2H) 0.89(s, 2H); ESI-MS M/z calculated 633.2345, Experimental 634.3(M +1)⁺(ii) a Retention time: 2.19 min; and (14S) -12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as the second enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 14) (3.0g, 54%);¹h NMR (400MHz, dimethylsulfoxide-d)₆)12.52(s, 1H), 8.22(d, J ═ 2.8Hz, 1H), 7.82(d, J ═ 8.2Hz, 1H), 7.58(dd, J ═ 8.5, 7.1Hz, 1H), 7.05(d, J ═ 7.2Hz, 1H), 6.99(s, 1H), 6.92(d, J ═ 8.2Hz, 1H), 6.71(d, J ═ 8.5Hz, 1H), 6.11(d, J ═ 2.8Hz, 1H), 4.31(t, J ═ 7.0Hz, 2H), 3.92(d, J ═ 12.6Hz, 1H), 3.15(s, 1H), 2.95(d, J ═ 13.2 Hz, 1H), 2.78-2.92 (d, J ═ 12.6Hz, 1H), 3.15(s, 1H), 2.95(d, J ═ 13.2, 1H), 2.78-2H, 1H), 1H (t, 10.6.6 Hz, 1H), 1H), 3.6H, 1H, 3.6H, 1H, 10H, 1H, 3.95 (d, 10H), 3.6H, 10H, 1, 2H) in that respect ESI-MS M/z calculated 633.2345, Experimental 634.1(M +1)⁺(ii) a Retention time: 2.2min (LC method B).

Example 5: preparation of 12, 12-dimethyl-8- (3- { [1- (trifluoromethyl) cyclopropyl]Methoxy } -1H-pyrazole-1-Base) -2. lambda.⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 15)

Step 1: 3- [ [1- (trifluoromethyl) cyclopropyl ] methoxy ] pyrazole-1-carboxylic acid tert-butyl ester

A5000 mL 3-neck round bottom flask was equipped with a mechanical stirrer, heating mantle, J-Kem temperature probe/controller, addition funnel, water-cooled reflux condenser, and nitrogen inlet/outlet. The vessel was charged with tert-butyl 5-oxo-1H-pyrazole-2-carboxylate (70g, 0.3800mol) and tetrahydrofuran (840mL, 12mL/g) under a nitrogen atmosphere to provide a clear pale yellow solution. Stirring was started and the pot temperature was recorded as 19 ℃. Subsequently charging the vessel with [1- (trifluoromethyl) cyclopropyl ] group]Methanol (58.56g, 0.4180mol), which was added undoped once, followed by triphenylphosphine (109.6g, 0.4180mol), which was added once as a solid, the resulting clear pale yellow solution was then treated with diisopropyl azodicarboxylate (clear orange-red liquid) added dropwise over 1h undoped (82.3mL, 0.4180mol), causing a gradual exotherm to 40 ℃ and a clear pale amber solution to result. Subsequently when analysis by LC/MS indicated complete exhaustion of the starting material, the reaction mixture was heated to a pot temperature of 50 ℃ and the conditions were maintained for 2h the clear amber reaction mixture was concentrated under reduced pressure and the resulting clear dark amber oil was suspended in toluene (560mL) and stirred at room temperature for 1h, during which time the solid precipitated (triphenylphosphine oxide MW 278.28.) the concentrated slurry was filtered through a glass frit buchner funnel and the filter cake was displacement washed with toluene (150mL) and then pumped for 30min the clear amber filtrate was concentrated under reduced pressure to provide a clear amber oil The material was purified by gradient elution from 0% hexane to 20% ethyl acetate/hexane, collecting 450mL fractions, eluting the product with approximately 5% ethyl acetate/hexane, combining the desired fractions and concentrating under reduced pressure to provide a clear pale yellow oil as the desired product, i.e. 3- [ [1- (trifluoromethyl) cyclopropyl ] amino acid]Methoxy radical]Pyrazole-1-carboxylic acid tert-butyl ester (81g, 0.264mol, 70%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)8.10(d, J ═ 2.9Hz, 1H), 6.14(d, J ═ 3.0Hz, 1H), 4.31(s, 2H), 1.55(s, 9H), 1.07(dp, J ═ 4.9, 1.3Hz, 4H), ESI-MS M/z calculated 306.11914, experimental value 307.0(M +1)⁺(ii) a Retention time: 1.75min (LC method B).

Step 2: 3- [ [1- (trifluoromethyl) cyclopropyl ] methoxy ] -1H-pyrazole

A5000 mL 3-neck round bottom flask was equipped with a mechanical stirrer, heating mantle, J-Kem temperature probe, water-cooled reflux condenser, addition funnel, and nitrogen inlet/outlet. Charging 3- [ [1- (trifluoromethyl) cyclopropyl ] group into a vessel under a nitrogen atmosphere]Methoxy radical]Pyrazole-1-carboxylic acid tert-butyl ester (80g, 0.2612mol), dichloromethane (320mL, 4mL/g), and methanol (320mL, 4mL/g) to provide a clear pale yellow solution. Stirring was started and the pot temperature was recorded as 19 ℃. the addition funnel was charged with 1, 4-dioxane containing 4M hydrochloric acid (195.9mL, 0.7836mol), which was then added dropwise over 1h, allowing a gradual exotherm to 30 ℃. When the reaction was complete as indicated by analysis by LC/MS, the resulting clear pale yellow solution was heated to a pot temperature of 45 ℃ and the conditions were maintained for 1h the reaction mixture was cooled to room temperature and then concentrated under reduced pressure the remaining residue was dissolved in tert-butyl methyl ether (640mL) and then transferred to a separatory funnel and partitioned with 2M sodium hydroxide solution (391.8mL, 0.7836 mol). The organic layer was removed and the residual aqueous solution was extracted with tert-butyl methyl ether (2X 200 mL). The combined organics were washed with a saturated solution of sodium chloride (500mL), dried over sodium sulfate (300g) and then filtered through a glass frit buchner funnel. The clear pale yellow filtrate was concentrated under reduced pressure to provide clarity A pale yellow oil which solidified upon standing to provide a white solid (49.5g, 0.240mol, 92%) as the desired product, i.e. 3- [ [1- (trifluoromethyl) cyclopropyl ] amino acid]Methoxy radical]-1H-pyrazole.¹H NMR (400MHz, dimethylsulfoxide-d)₆)11.90(s, 1H), 7.51(d, J ═ 2.4Hz, 1H), 5.67(d, J ═ 2.4Hz, 1H), 4.19(s, 2H), 1.09-0.97(M, 4H), ESI-MS M/z calculated 206.0667, experimental 207.0(M +1)⁺(ii) a Retention time: 1.08min (LC method B).

And step 3: 2-chloro-6- [3- [ [1- (trifluoromethyl) cyclopropyl ] methoxy ] pyrazol-1-yl ] pyridine-3-carboxylic acid tert-butyl ester

A5000 mL 3-necked round bottom flask was equipped with a mechanical stirrer, a cooling bath as an auxiliary containment, a J-Kem temperature probe, a water-cooled reflux condenser, an addition funnel, and a nitrogen inlet/outlet, and the vessel was charged with 3- [ [1- (trifluoromethyl) cyclopropyl ] under a nitrogen atmosphere]Methoxy radical]-1H-pyrazole (45g, 0.2183mol) and N, N-dimethylformamide (540mL, 12mL/g), providing a clear pale yellow solution. Stirring was started and the pot temperature was recorded as 17 ℃. The vessel was then charged with tert-butyl 2, 6-dichloropyridine-3-carboxylate (54.16g, 0.2183mol) in solid form, added in one portion, followed by potassium carbonate (39.22g, 0.2838mol) (added in one portion in solid form), followed by 1, 4-diazabicyclo [2.2.2 ] ]Octane (3.67g, 0.03274mol) (added in one portion as a solid) treated the resulting clear pale yellow solution, the resulting pale yellow suspension was stirred at room temperature for 24h, the reaction mixture was cooled to 10 ℃ with a crushed ice/water cooling bath. Water (540mL) was charged to the addition funnel, added dropwise over 45min, resulting in a thick suspension and allowing the exotherm to 15 ℃. the resulting suspension was stirred for a further 30min at 15 ℃ and then filtered through a glass frit buchner funnel. The filter cake was displacement washed with water (2X 500mL) and subsequently pumped in a Buhner funnel for 2 h. The material was then air dried overnight to afford a white particulate solid (73g, 0.175mol, 80%) that was 2-chloro-6- [3- [ [1- (trifluoromethyl) cyclopropyl ] methyl ester]Methoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid tert-butyl esterESI-MS M/z calculated 417.1067, Experimental 418.1(M +1)⁺(ii) a Retention time: 0.85min (LC method A).

And 4, step 4: 2-chloro-6- [3- [ [1- (trifluoromethyl) cyclopropyl ] methoxy ] pyrazol-1-yl ] pyridine-3-carboxylic acid

A1000 mL 3-neck round bottom flask was equipped with a mechanical stirrer, heating mantle, J-Kem temperature probe/controller, addition funnel, water-cooled reflux condenser, and nitrogen inlet/outlet the vessel was charged with 2-chloro-6- [3- [ [1- (trifluoromethyl) cyclopropyl ] under a nitrogen atmosphere ]Methoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (70g, 0.1675 mol) and 2-propanol (350mL) to provide an off-white suspension stirring is started and the pot temperature is recorded as 19 ℃. an addition funnel is charged with 6M aqueous hydrochloric acid (139.6mL, 0.8375mol), which is added dropwise over 10min, causing an exotherm to 30 ℃. the resulting suspension is then heated to reflux (pot temperature about 82 ℃). after heating, the suspension becomes a clear pale yellow solution (at about 75 ℃). the pot temperature is then stirred for about 30min under reflux, the solids begin to precipitate, the suspension is continued to be stirred under reflux for another 30min, at which time water (210mL) is added dropwise over 15min, heat is then removed, and the suspension is continued to be stirred and allowed to slowly cool to room temperature The filter cake was then displacement washed with water (2X 100mL) and then pumped through a Buhner funnel for 30min. the material was further dried in a vacuum oven at 45 ℃ for 24h to provide 2-chloro-6- [3- [ [1- (trifluoromethyl) cyclopropyl ] as a white solid]Methoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (56g, 0.155mol, 92%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)13.64(s, 1H), 8.44(d, J ═ 2.9Hz, 1H), 8.41(d, J ═ 8.4Hz, 1H), 7.74(d, J ═ 8.4Hz, 1H), 6.24(d, J ═ 2.9Hz, 1H), 4.41(s, 2H), 1.16-1.07(M, 4H), ESI-MS M/z calculated 361.0441, experimental 362.1(M +1) ⁺(ii) a Retention time: 0.66min (LC method A).

And 5: 4- [3- [ [6- [ [ 2-chloro-6- [3- [ [1- (trifluoromethyl) cyclopropyl ] methoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- [ [1- (trifluoromethyl) cyclopropyl group]Methoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (260mg, 0.6973mmol) and carbonyldiimidazole (113.1mg, 0.6973mmol) were combined in tetrahydrofuran (3.783mL) and stirred at 45 ℃ for 1h, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (287.7mg, 0.6973mmol) followed by the addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (212.4mg, 208.6 μ L, 1.395mmol) and the reaction was heated at 45 ℃ for 4 h, the reaction was diluted with ethyl acetate and washed with 1M citric acid solution followed by brine the organics were separated, dried over sodium sulfate, evaporated and then purified by silica gel chromatography (24 g column) using a gradient of 100% hexane to 70% ethyl acetate/hexane to give 4- [3- [ [6- [ [ 2-chloro-6- [3- [ [1- (trifluoromethyl) cyclopropyl ] as a white solid]Methoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical ]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (232mg, 44%).¹H NMR (400MHz, dimethylsulfoxide-d)₆) 12.78(s, 1H), 8.41(d, J ═ 2.4Hz, 1H), 8.11(d, J ═ 8.3Hz, 1H), 7.72(d, J ═ 8.3Hz, 1H), 7.62(dd, J ═ 8.4, 7.3Hz, 1H), 7.21(s, 1H), 7.17(d, J ═ 7.1Hz, 1H), 6.74(d, J ═ 8.5Hz, 1H), 6.23(s, 1H), 4.39(s, 2H), 3.58-3.46(m, 1H), 3.24(s, 2H), 2.74(t, J ═ 10.5Hz, 1H), 2.02(s, 1H), 1.79(td, J ═ 12.2, 6.4, 1H), 1.50 (t, J ═ 10.5Hz, 1H), 2.02(s, 1H), 1.79(td, 12.2, 6.4, 1H), 1H, 13 (d, 1H), 11.13H, 11H), 11H, 1H, 13 (d, 1H), experimental value 756.5(M +1)⁺(ii) a Retention time: 2.31min (LC method E).

Step 6: 12, 12-dimethyl-8- (3- { [1- (trifluoromethyl) cyclopropyl]Methoxy } -1H-pyrazol-1-yl) -2 lambda⁶- Thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 15)

Part A: 4- [3- [ [6- [ [ 2-chloro-6- [3- [ [1- (trifluoromethyl) cyclopropyl ] methoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (232mg, 0.3068mmol) was dissolved in dichloromethane (5.0mL), and hydrochloric acid (4M in dioxane) (2.5 mL, 4M, 10.00mmol) was added to the mixture and stirred at room temperature for 3h, the reaction was concentrated to dryness under reduced pressure, redissolved in ethyl acetate, and then 2M aqueous sodium carbonate (5mL) was added to adjust the solution to a pH of about 10 the organic layer was extracted with ethyl acetate (2 × 10mL), washed with brine, dried over sodium sulfate, and evaporated to dryness under reduced pressure.

And part B: to a vial was added the crude amine from part A, potassium carbonate (235mg, 1.70mmol), cesium fluoride (75.3mg, 0.4957mmol),

Molecular sieves and dimethyl sulfoxide (7.0 mL.) the vial was purged with nitrogen, capped, heated to 150 ℃ and stirred for 16 h. The reaction was cooled to room temperature the reaction was diluted with ethyl acetate and washed with 1M citric acid solution followed by brine. The organics were separated, dried over sodium sulfate, evaporated, and then purified by silica gel chromatography (24 g column) using a gradient of 100% hexane to 80% ethyl acetate to give 12, 12-dimethyl-8- (3- { [1- (trifluoromethyl) cyclopropyl) as an off-white solid]Methoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 15) (101.9mg, 54%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.51(s，1H)，8.22(d，J＝2.8Hz，1H)，7.82(d，J＝8.2Hz， 1H)，7.66-7.49(m，1H)，7.05(d, J ═ 7.2Hz, 1H), 6.98(d, J ═ 5.5Hz, 1H), 6.92(d, J ═ 8.2Hz, 1H), 6.71(d, J ═ 8.4Hz, 1H), 6.16(d, J ═ 2.7Hz, 1H), 4.36(q, J ═ 11.9Hz, 2H), 3.92(dd, J ═ 24.2, 10.9Hz, 1H), 3.24-3.07(m, 1H), 2.95(d, J ═ 13.0Hz, 1H), 2.78-2.64(m, 1H), 2.22-2.08(m, 1H), 1.86(dd, J ═ 11.8, 5.0, 1H), 1.76(dd, 15.65, J ═ 1.9, 1H), 1.22-2.08 (m, 1H), 1.86(dd, J ═ 11.8, 5.0, 1H), 1.76(dd, 1H), 1.6.5, 1H), 1.5.6, 1H), 1H, 1. ESI-MS M/z calculated 619.2189, Experimental 620.2(M +1) ⁺(ii) a Retention time: 2.1 min (LC method E).

Example 6: preparation of 12, 12-dimethyl-8- (3- { [1- (trifluoromethyl) cyclopropyl]Methoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 21) and 12, 12-dimethyl-8- (3- { [1- (trifluoromethyl) cyclopropyl]Methoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 22)

Step 1: 12, 12-dimethyl-8- (3- { [1- (trifluoromethyl) cyclopropyl]Methoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 21) and 12, 12-dimethyl-8- (3- { [1- (trifluoromethyl) cyclopropyl]Methoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 22)

Racemic 12, 12-dimethyl-8- (3- { [1- (trifluoromethyl) cyclopropyl) -8- (250X 21.2mm column, 5 μm particle size) was purified using ChiralPak AS-H (250X 21.2mm column) and 20% acetonitrile (no modifier)/80% carbon dioxide mobile phase (70mL/min)]Methoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (Compound 15) (82.4mg, 0.133mmol) was subjected to chiral SFC chromatography to give 12, 12-dimethyl-8- (3- { [1- (trifluoromethyl) cyclopropyl-ketone as the first enantiomer to be eluted as an off-white solid]Methoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 21) (32.38mg, 78%);¹h NMR (400MHz, dimethylsulfoxide-d)₆)12.51(s, 1H), 8.22(d, J ═ 2.7Hz, 1H), 7.82(d, J ═ 8.2Hz, 1H), 7.72-7.67(m, 1H), 7.62-7.50(m, 1H), 7.05(d, J ═ 7.0Hz, 1H), 6.92(d, J ═ 8.2Hz, 1H), 6.70(d, J ═ 8.5Hz, 1H), 6.15(d, J ═ 2.7, 1H), 4.36 (q, J ═ 11.9Hz, 2H), 4.16-4.12(m, 1H), 3.22-3.10(m, 1H), 2.95(d, J ═ 12.9Hz, 1H), 2.74-2.68(m, 1H), 2.03, 2.20 (m, 2.5H), 3.5 (m, 1H), 3.5 (ddh), 3.5H, 1H), 3.5 (d, 1H), 2.5 (d, 3.5H, 1H), 3.5H, 5 (ddh, 1H), j ═ 5.1Hz, 2H), ESI-MS M/z calculated 619.2189, experimental 620.2(M +1) ⁺(ii) a Retention time: 2.1min (LC method E) and 12, 12-dimethyl-8- (3- { [1- (trifluoromethyl) cyclopropyl-l-propyl ] as an off-white solid as the second enantiomer to be eluted]Methoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 22) (34.58mg, 83%);¹h NMR (400MHz, dimethylsulfoxide-d)₆) 12.51(s，1H)，8.22(d，J＝2.8Hz，1H)，7.82(d，J＝8.3Hz，1H)，7.69(d，J＝3.6Hz，1H)，7.57(t，J＝78Hz, 1H), 7.05(d, J ═ 7.2Hz, 1H), 6.92(d, J ═ 8.3Hz, 1H), 6.71 (d, J ═ 8.5Hz, 1H), 6.16(d, J ═ 2.8Hz, 1H), 4.36(q, J ═ 11.9Hz, 2H), 4.14(d, J ═ 2.3 Hz, 1H), 3.16(s, 1H), 2.95(d, J ═ 13.4Hz, 1H), 2.76-2.68(M, 1H), 2.19-2.07(M, 1 ddh), 1.86 (J ═ 11.8, 5.1Hz, 1H), 1.75(s, 1H), 1.60(s, 3H), 1.51(s, 3H), 1.28 (s, J ═ 2.8, 5.1H), 1H, 1.75(s, 1H), 1.60(s, 3H), 1.51(s, 3H), 28(d, J ═ 2.2, 2H), 7, 2H, 1H, 2(M ═ 2, 1H), 2, 1H, 2, 1H), 2, 1H, 2, 1H⁺(ii) a Retention time: 2.1min (LC method E).

Example 7: preparation of 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.111, 14.05, 10 ]Pentacosane-1 (23), 5, 7, 9, 20(24), 21-hexaene-2, 2, 4-trione (compound 28)

Step 1: 1- (bromomethyl) -2-oxocyclopentanecarboxylic acid ethyl ester

A solution of ethyl 2-oxocyclopentanecarboxylate (70g, 449mmol) in dry tetrahydrofuran (300mL) was slowly added to a suspension of 67.6% sodium hydride/mineral oil suspension (19.17g, 540mmol) in tetrahydrofuran (750mL) containing hexamethylphosphoramide (97g, 540mmol) under an argon atmosphere at room temperature the reaction mixture was stirred at room temperature for 1 h. Dibromomethane (392g, 250mmol) was added and the reaction mixture was refluxed at 80 ℃ for 16h. The reaction was cooled to room temperature and diethyl ether (1000mL) was added, and the organic layer was washed with water (5 × 500mL), dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography using 0-10% hexane-ethyl acetate to provide ethyl 1- (bromomethyl) -2-oxocyclopentanecarboxylate as a colorless oil (85g, 76%).¹H NMR(250MHz，CDCl₃)4.18(q，J＝7.0Hz，7.25Hz，2H)；3.68(q，J＝22.5Hz，J＝9.5Hz，2H)；2.58-2.00(m，6H)；1.25(t，J＝7.75Hz，3H)。

Step 2: 2-Methyleneadipic acid diethyl ester

Potassium carbonate (79g, 572mmol) was added to a solution of ethyl 1- (bromomethyl) -2-oxocyclopentanecarboxylate (85g, 341mmol) in anhydrous ethanol (680mL) and the mixture was stirred at room temperature for 16h the mixture was filtered, evaporated and purified by silica gel column chromatography using 0-5% hexane-ethyl acetate to give diethyl 2-methyleneadipate as a colorless oil (72.7g, 98%). ¹H NMR(250MHz，CDCl₃)6.16 (s，1H)；5.54(s，1H)；4.24-4.07(m，4H)；2.36-2.28(m，4H)，1.83-1.77(m，2H)， 1.32-1.21(m，6H)。

And step 3: 2- (2-methyl-2-nitropropyl) adipic acid diethyl ester

1, 8-diazabicycloundec-7-ene (23g, 151mmol) was added to a solution of diethyl 2-methyleneadipate (72.7g, 340mmol) and 2-nitropropane (36.3g, 408mmol) in anhydrous acetonitrile (1000mL), and the mixture was stirred at room temperature for 16h. The organic phase was concentrated and purified by silica gel column chromatography using 0-10% hexane-ethyl acetate to provide diethyl 2- (2-methyl-2-nitropropyl) adipate as a colorless oil (86g, 84%).¹H NMR(250MHz，CDCl₃)4.17-4.07(m，4H)；2.41- 2.05(m，5H)，1.72-1.44(m，4H)，1.56(s，3H)，1.51(s，3H)，1.28-1.21(m，6H)。

And 4, step 4: 4- (4, 4-dimethyl-5-oxo-pyrrolidin-2-yl) -butyric acid ethyl ester

A mixture of diethyl 2- (2-methyl-2-nitropropyl) adipate (43 g, 141.7mmol) and Raney nickel slurry (12g) in ethanol (860mL) was heated in a Barr reactor under 2 bar of hydrogen at 80 ℃ for 18h, celite (50g) was added and the resulting mixture was filtered, the solids were discarded and the filtrate was concentrated to obtain 4- (4, 4-dimethyl-5-oxo-pyrrolidin-2-yl) -butyric acid ethyl ester (31.2g, 97%) as an orange oil the crude product was used in the next step without further purification ESI-MS M/z calculated 227.3, experimental 228.3 (M +1) ⁺. Retention time: 3.23min (LC method Q).

And 5: 4- (4, 4-dimethylpyrrolidin-2-yl) -butan-1-ol

Lithium aluminum hydride (39.3g, 1036.0mmol) was added portionwise to a solution of 4- (4, 4-dimethyl-5-oxo-pyrrolidin-2-yl) -butyric acid ethyl ester (78.8g, 345.3 mmol) in tetrahydrofuran (1200mL) over a 45min period and the resulting slurry was heated to reflux under nitrogen for 18h. The solid was discarded and the filtrate was concentrated in vacuo to give 4- (4, 4-dimethylpyrrolidin-2-yl) -butan-1-ol as a brown oil (51.5g, 87%). The crude product was used in the next step without further purification. ESI-MS M/z calculated 171.28, Experimental 172.3 (M +1)⁺. Retention time: 1.05min (LC method Q).

Step 6: 2- (4-hydroxybutyl) -4, 4-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of 4- (4, 4-dimethylpyrrolidin-2-yl) -butan-1-ol (51.5g, 301mmol) in dichloromethane (400mL) was addedA solution of sodium bicarbonate (50.6g, 602mmol) in water (300mL) was added, followed by di-tert-butyl dicarbonate (65.6g, 301 mmol). The resulting biphasic mixture was stirred at room temperature for 18h. The phases were separated and the aqueous phase was discarded. The organic phase was concentrated and purified by silica gel column chromatography using 0-45% hexane-ethyl acetate to give tert-butyl 2- (4-hydroxybutyl) -4, 4-dimethyl-pyrrolidine-1-carboxylate (57.2 g, 77%) as a clear oil. ¹H NMR(250MHz，CDCl₃)4.35(t, 1H), 3.53(M, 1H), 3.37(M, 2H), 2.76 (M, 1H), 2.01-1.81(M, 2H), 1.40-1.24(M, 23H). ESI-MS M/z calculated 271.4, experimental 272.4(M +1)⁺Retention time: 4.67min (LC method Q).

And 7: 2, 2-dimethyl-4- (4-methylsulfonyloxybutyl) pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of 4- (4-hydroxybutyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.28g, 8.401mmol) in dichloromethane (19mL) and triethylamine (8.0mL, 57mmol) cooled to 0 ℃ was added methanesulfonyl chloride (2.161mL, 27.92mmol) dropwise, the reaction mixture was stirred for 20h, after 1h the reaction was allowed to warm to room temperature (clear solution became cloudy orange after 10 min), the reaction mixture was quenched with ice water and dichloromethane, then brine, the aqueous layer was further extracted with dichloromethane (2 × 20mL), and the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was dried in vacuo for 1h to provide tert-butyl 2, 2-dimethyl-4- (4-methylsulfonyloxybutyl) pyrrolidine-1-carboxylate (2.9g, 99%) as a yellow oil (ESI-MS M/z calculated 349.1923, Experimental 350.2(M +1)⁺(ii) a Retention time: 1.82min (LC method E).

And 8: 4- (4-Aminobutyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

Tert-butyl 2, 2-dimethyl-4- (4-methylsulfonyloxybutyl) pyrrolidine-1-carboxylate (2.9g, 8.298 mmol) was dissolved in a mixture of dioxane (60mL) and ammonium hydroxide (60mL, 30% weight/volume, 510mmol) the mixture was heated to 50 ℃ in a sealed vessel for 18 h. Dioxane was concentrated in vacuo and dichloromethane (50mL) was added. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (80 g column) using a dichloromethane-methanol (containing 5 mL/L30% ammonium hydroxide) gradient (0 to 15% methanol/dichloromethane) to give tert-butyl 4- (4-aminobutyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (1.44g, 64%) as an off-white foam.¹H NMR (400MHz, dimethylsulfoxide-d)₆) 7.90(s, 2H), 3.55(dd, J ═ 18.7, 11.1Hz, 1H), 3.34(s, 2H), 3.17(s, 1H), 2.76(dd, J ═ 17.0, 9.5Hz, 2H), 2.06(s, 1H), 1.95-1.74(M, 1H), 1.52(t, J ═ 18.4Hz, 2H), 1.39(d, J ═ 9.9Hz, 9H), 1.35(s, 1H), 1.34(s, 2H), 1.31-1.18(M, 6H), ESI-MS M/z calculated value 270.23074, experimental value 271.2(M +1)⁺(ii) a Retention time: 1.21min (LC method E).

And step 9: 2, 2-dimethyl-4- [4- [ (6-sulfamoyl-2-pyridyl) amino ] butyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

In a 250mL flask, under nitrogen and reflux condenser, 6-fluoropyridine-2-sulfonamide (894mg, 5.07 mmol) was combined in dimethyl sulfoxide (20mL), followed by potassium carbonate (1.1g, 8.0mmol) and tert-butyl 4- (4-aminobutyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (1.44g, 5.33mmol). The vessel was heated in an oil bath at 60 ℃ for 18 h. Potassium carbonate (1.1g, 8.0mmol) was added and heated to 80 ℃ for an additional 4h after cooling, the reaction mixture was filtered, then diluted with ethyl acetate and washed with 1M citric acid solution followed by brine the organics were separated, dried over sodium sulfate, filtered, evaporated and purified by silica gel chromatography (80 g column GOLD) using a gradient of 100% hexane to 75% ethyl acetate/hexane to give a white solid2, 2-dimethyl-4- [4- [ (6-sulfamoyl-2-pyridyl) amino group of (1)]Butyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (475mg, 22%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)7.51(dd, J ═ 8.4, 7.3Hz, 1H), 7.07(s, 2H), 6.94(t, J ═ 5.7Hz, 2H), 6.61(d, J ═ 8.2Hz, 1H), 3.54(dd, J ═ 18.2, 8.5Hz, 1H), 3.28 (dd, J ═ 12.6, 6.6Hz, 2H), 2.78(dd, J ═ 19.7, 10.1Hz, 1H), 2.07(s, 1H), 1.94-1.80 (M, 1H), 1.52(s, 2H), 1.44(d, J ═ 12.2Hz, 1H), 1.38(d, J ═ 10.4Hz, 9H), 1.35(d, J ═ 10.9, 6H), 1.21H, 21, 17H, 17 Hz, 17H), experimental calculated values (M, 1H, 17H, 18 Hz, 1H, 11H, 18H) ⁺(ii) a Retention time: 1.76min (LC method E).

Step 10: 4- [4- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] butyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (425mg, 1.13mmol) and carbonyldiimidazole (217mg, 1.34mmol) were combined in tetrahydrofuran (7mL) and stirred at 50 ℃ for 90 min. Followed by addition of 2, 2-dimethyl-4- [4- [ (6-sulfamoyl-2-pyridyl) amino]Butyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (475mg, 1.11mmol) was added followed by 1, 8-diazabicyclo [5.4.0]Undec-7-ene (350 μ L, 2.34mmol) and the reaction heated at 50 ℃ for 18 h.the reaction was diluted with ethyl acetate and washed with 1M citric acid solution followed by brine the organics were separated, dried over sodium sulfate, filtered and evaporated and then purified by silica gel chromatography (80 g column) using a gradient of 100% hexane to 70% ethyl acetate/hexane to give 4- [4- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical ]-2-pyridyl]Amino group]Butyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (613mg, 83%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.80 (s，1H) 8.41(t, J ═ 3.0Hz, 1H), 8.11(d, J ═ 8.4Hz, 1H), 7.71(d, J ═ 8.4Hz, 1H), 7.61(dd, J ═ 8.4, 7.3Hz, 1H), 7.22(s, 1H), 7.16(d, J ═ 7.0Hz, 1H), 6.73(d, J ═ 8.5 Hz, 1H), 6.18(d, J ═ 2.9Hz, 1H), 4.34(t, J ═ 7.0Hz, 2H), 3.54-3.42(m, 1H), 3.22(t, J ═ 6.8Hz, 2H), 2.72-2.63(m, 1H), 2.08(t, J ═ 7.1, 2H), 1.88 (t, 1H), 1.5 (t, 1H), 1.11.5H, 1H), 1.11.11.5 (d, 1H), 1H, 6.5 (t, 1H), 4H) 0.98-0.92(M, 2H), 0.88 (s, 2H). ESI-MS M/z calculated 783.27924, Experimental 784.2(M +1)⁺(ii) a Retention time: 2.4min (LC method E).

Step 11: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.111, 14.05, 10]Pentacosane-1 (23), 5, 7, 9, 20(24), 21-hexaene-2, 2, 4-trione (compound 28)

Part A: 4- [4- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] butyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (538 mg, 0.686mmol) was dissolved in dichloromethane (12mL), and hydrochloric acid (4M in dioxane) (5mL, 4M, 20.0mmol) was added to the mixture and stirred at room temperature for 1 h. The mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate, then 2M aqueous sodium carbonate (5mL) was added to bring the pH to about 10, extracted with ethyl acetate (2 × 10mL), washed with brine, then dried over sodium sulfate, filtered, and evaporated to dryness under reduced pressure.

And part B: the material from part A was combined with potassium carbonate (474mg, 3.43mmol), cesium fluoride (156 mg, 1.03mmol),

Molecular sieves and dimethylsulfoxide (11mL) were combined in vialsPurged with nitrogen, capped, heated to 150 ℃ and stirred for 18h. The reaction was diluted with ethyl acetate and washed with 1M citric acid solution followed by brine. The organics were separated, dried over sodium sulfate, filtered and evaporated, then purified by silica gel chromatography (40 g column) using a gradient of 100% hexane to 80% ethyl acetate/hexane to give 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (compound 28) (270mg, 60%).¹H NMR (400 MHz, dimethylsulfoxide-d)₆)12.45(s, 1H), 8.21(d, J ═ 2.7Hz, 1H), 7.86(d, J ═ 8.3Hz, 1H), 7.69(t, J ═ 7.9Hz, 1H), 7.23(d, J ═ 7.2Hz, 1H), 6.93(d, J ═ 8.3Hz, 1H), 6.81(d, J ═ 8.4Hz, 1H), 6.12(d, J ═ 2.7Hz, 1H), 4.32(t, J ═ 7.0Hz, 2H), 3.51(s, 2H), 3.30(s, 1H), 2.76(d, J ═ 15.3Hz, 1H), 2.69-2.58(m, 1H), 2.14(d, J ═ 7.4, 1H), 2.5 (t, J ═ 2.5H), 6.5 (d, J ═ 6.7H, 1H), 1H, 6.5 (d, 2.7, 6.7, 6.5H, 6.7H, 1H, 2H) in that respect ESI-MS M/z calculated 647.2502, Experimental 648.2(M +1) ⁺(ii) a Retention time: 2.26min (LC method E).

Example 8: preparation of 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 29) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 30)

Step 1: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 29) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 30)

Racemic 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] 8 using ChiralPak AS-H (250X 21.2mm column, 5 μm particle size) and 30% acetonitrile: methanol (90: 10)/70% carbon dioxide mobile phase (0.5mL/min)]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.111, 14.05, 10]Eicosapentaenoic-1- (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (Compound 28) (204mg, 0.3150mmol) was subjected to chiral SFC chromatography to give 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] ketone as the first enantiomer to be eluted as an off-white solid]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 29) (94.1mg, 91%); ESI-MS M/z calculated 647.2502, Experimental 648.2(M +1)⁺(ii) a Retention time: 2.27min (LC method E) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as an off-white solid as the second enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.111, 14.05, 10 ]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 30) (90.0)mg，87％)；¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.45(s, 1H), 8.21(d, J ═ 2.8Hz, 1H), 7.86(d, J ═ 8.3Hz, 1H), 7.69(t, J ═ 7.9Hz, 1H), 7.23 (d, J ═ 7.2Hz, 1H), 6.93(d, J ═ 8.3Hz, 1H), 6.81(d, J ═ 8.1Hz, 2H), 6.12(d, J ═ 2.7 Hz, 1H), 4.32(t, J ═ 7.0Hz, 2H), 3.29(dd, J ═ 4.7, 2.4Hz, 1H), 2.86-2.69(m, 1H), 2.63 (t, J ═ 16.0, 11.6, 1H), 2.13(s, 2.13, 2.5H), 2.5 (d, 1.5H), 1H, 5(dd, 5H, 5H), 5(d, 1H, 2.5, 5(dd, 1H, 2.5H, 1H, 2.5, 1H, 5H, 1H, 5, 1H, 2H, 1H, 2, 3.7Hz, 2H), 0.93(d, J ═ 9.2Hz, 1H), 0.88(t, J ═ 5.8Hz, 2H), ESI-MS M/z calculated 647.2502, experimental 648.2(M +1)⁺(ii) a Retention time: 2.27min (LC method E).

Example 9: preparation of 12, 12, 17-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (diastereomer pair 1) (compound 35), 12, 17-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (diastereomer pair 2) (compound 36), 12, 17-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (diastereomer pair 1, enantiomer 1) (compound 58), 12, 17-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (diastereomer pair 1, enantiomer 2) (compound 59), 12, 17-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (diastereomer pair 2, enantiomer 1) (compound 60) and 12, 12, 17-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (diastereomer pair 2, enantiomer 2) (compound 61)

Step 1: (3E) -3- (hydroxymethylene) -6-methyl-tetrahydropyran-2-one (sodium salt)

To a suspension of sodium hydride (60% in mineral oil) (2.63g, 60% w/w, 65.8mmol) in diethyl ether (56 mL) was added pure ethanol (300. mu.L), followed by dropwise addition of a mixture of 6-methyltetrahydrofuran-2-one (5.0g, 43.80mmol) and ethyl formate (6.0mL, 74mmol) at ambient temperature over 30 min. After the addition was complete, the reaction mixture was stirred at room temperature for 1 h. The solid formed in the mixture (sodium salt of product) was collected by filtration, washed with diethyl ether and dried under high vacuum to give (3E) -3- (hydroxymethylene) -6-methyl-tetrahydropyran-2-one (sodium salt) (7.1g, 99%). ESI-MS M/z calculated 142.06299, Experimental 143.2(M +1)⁺(ii) a Retention time: 0.64min (LC method E).

Step 2: 6-methyl-3-methylene-tetrahydropyran-2-one

Mixing (3E) -3- (hydroxy methylene) -6-methyl-tetrahydropyran-2-one (sodium) Salt) (7.1g, 43mmol) was suspended in tetrahydrofuran (100mL), treated with paraformaldehyde (4.2g, 140mmol) under nitrogen and the mixture was heated to 65 ℃ for 1 h. The mixture was cooled in an ice-water bath, quenched with saturated aqueous solution of potassium carbonate (20mL) and the organic phase was separated, followed by extraction of the aqueous phase with diethyl ether (4 × 10 mL). The organic fractions were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure by rotary evaporation without heating the obtained residue was purified by silica gel chromatography (120 g column) using a gradient of 100% hexane to 40% ethyl acetate/hexane to give 6-methyl-3-methylene-tetrahydropyran-2-one (2.96g, 55%) as a colorless liquid.¹H NMR(400MHz，CDCl₃)6.48-6.38(m, 1H), 5.57(dt, J ═ 2.7, 1.5Hz, 1H), 4.49(dqd, J ═ 10.4, 6.3, 2.6Hz, 1H), 2.71(dddt, J ═ 16.2, 5.0, 3.5, 1.3Hz, 1H), 2.65-2.52(m, 1H), 2.03-1.93(m, 1H), 1.67(dddd, J ═ 13.9, 12.4, 10.5, 5.1Hz, 1H), 1.40(d, J ═ 6.3Hz, 3H). ESI-MS M/z calculated 126.06808, Experimental 127.0(M +1)⁺(ii) a Retention time: 0.66min (LC method E).

And step 3: 6-methyl-3- (2-methyl-2-nitro-propyl) tetrahydropyran-2-one

2-Nitropropane (2.6mL, 29mmol) was treated with 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene (550 μ L, 3.68mmol) and stirred under nitrogen for 5min, followed by dropwise addition of a solution of 6-methyl-3-methylene-tetrahydropyran-2-one (2.96g, 23.5mmol) in acetonitrile (32mL) at room temperature over 45min the solution was stirred at room temperature for 4h. The mixture was evaporated and the residue was subsequently purified by silica gel chromatography (120 g column) using a gradient of 100% hexane to 60% ethyl acetate/hexane to isolate the product, which was then dried in vacuo to give 6-methyl-3- (2-methyl-2-nitro-propyl) tetrahydropyran-2-one (4.32g, 85%) as a clear oil which turned into a white solid upon standing.¹H NMR(400MHz，CDCl₃)4.57-4.37(m，1H)，2.71-2.58 (m，1H)，2.51-2.32(M, 1H), 2.24(dd, J ═ 15.0, 6.9Hz, 1H), 2.14-2.06(M, 1H), 2.00-1.87(M, 1H), 1.68-1.60(M, 6H), 1.58(dd, J ═ 4.8, 2.7Hz, 1H), 1.56-1.47(M, 1H), 1.36(dd, J ═ 6.2, 3.2Hz, 3H), ESI-MS M/z calculated value 215.11575, experimental value 216.2 (M +1)⁺(ii) a Retention time: 1.11min (LC method E).

And 4, step 4: 3- (3-hydroxybutyl) -5, 5-dimethyl-pyrrolidin-2-one

6-methyl-3- (2-methyl-2-nitro-propyl) tetrahydropyran-2-one (4.32g, 20.07mmol) was dissolved in ethanol (78mL) and wet Raney nickel (1.2g, 20.45mmol) was added under a nitrogen atmosphere. Three vacuum/hydrogen cycles were performed and the resulting mixture was stirred at room temperature under hydrogen (1 atmosphere) for 10 min. The suspension was then equipped with a reflux condenser and heated to 60 ℃ and stirred at this temperature under hydrogen for 24h. The filtrates were combined and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (120 g column) using a gentle gradient of 100% dichloromethane to 10% methanol/dichloromethane to give 3- (3-hydroxybutyl) -5, 5-dimethyl-pyrrolidin-2-one as a white solid (2.5g, 67%). ¹H NMR (400MHz, dimethylsulfoxide-d)₆)7.63(s, 1H), 4.36(d, J ═ 4.7Hz, 1H), 3.56(dt, J ═ 11.9, 6.0Hz, 1H), 2.35(qd, J ═ 9.3, 4.4Hz, 1H), 2.01(dd, J ═ 12.3, 8.6Hz, 1H), 1.85-1.59(m, 1H), 1.45-1.35(m, 1H), 1.31(ddd, J ═ 10.6, 8.1, 4.1Hz, 2H), 1.28-1.20 (m, 1H), 1.18(s, 3H), 1.13(s, 3H), 1.03(dd, J ═ 6.2, 1.6Hz, 3H). ESI-MS M/z calculated 185.14159, Experimental 186.2(M +1)⁺(ii) a Retention time: 0.74min (LC method E).

And 5: 4- (5, 5-dimethylpyrrolidin-3-yl) butan-2-ol

A solution of 3- (3-hydroxybutyl) -5, 5-dimethyl-pyrrolidin-2-one (2.5g, 13.49 mmol) in anhydrous tetrahydrofuran (37mL) was carefully added (within 20 min) to a suspension of lithium aluminum hydride (686.6mg, 20.24mmol) in anhydrous tetrahydrofuran (37mL) at room temperature under a nitrogen atmosphere after the addition was complete, the reaction mixture was heated to reflux for 72h (two additional portions of lithium aluminum hydride (200mg, 7.00mmol) were added to the reaction mixture after 24h and 48h of reflux). Cooling the mixture in an ice-water bath; tetrahydrofuran (25mL) was again added to the mixture followed by slow addition of saturated aqueous solution of sodium potassium tartrate tetrahydrate (as the schel salt (Rochelle's), 30 mL.) the resulting mixture was stirred vigorously at room temperature for 2h until significant separation of the aqueous and organic phases was achieved; the organic layer was then separated and concentrated in vacuo the residue was dissolved in dichloromethane (100mL) and the resulting solution was washed with brine (2 x 15mL) the organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 4- (5, 5-dimethylpyrrolidin-3-yl) butan-2-ol as a yellow oil (1.6g, 69%). ¹H NMR(400MHz，CDCl₃)3.78(dd, J ═ 11.9, 5.8Hz, 1H), 3.14(ddd, J ═ 10.4, 7.6, 2.8Hz, 1H), 2.59(dd, J ═ 11.0, 8.1Hz, 1H), 2.24-2.07(M, 1H), 1.87-1.78 (M, 1H), 1.73(s, 2H), 1.54-1.37(M, 4H), 1.37-1.21(M, 1H), 1.21-1.13(M, 9H), ESI-MS M/z calculated 171.16231, experimental 172.2(M +1)⁺(ii) a Retention time: 0.53min (LC method E).

Step 6: 4- (3-hydroxybutyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

Di-tert-butyl dicarbonate (2.4mL, 10.45mmol) and triethylamine (1.7mL, 12.20mmol) are added to a solution of 4- (5, 5-dimethylpyrrolidin-3-yl) butan-2-ol (1.6g, 9.341mmol) dissolved in dichloromethane (40 mL) at 0 deg.C the reaction mixture is allowed to warm to room temperature and stirred for 30min, the mixture is washed with water (15mL), saturated sodium bicarbonate (15mL) and brine (15mL), the organics are then extracted, dried over sodium sulfate, filteredAnd the mixture was concentrated. The residue was purified by silica gel chromatography (40 g column) using a gradient of 100% dichloromethane to 10% methanol/dichloromethane to isolate tert-butyl 4- (3-hydroxybutyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (2.4g, 95%) as a clear oil.¹H NMR(400MHz，CDCl₃)3.79(s, 1H), 3.75-3.56 (m, 1H), 3.00-2.77(m, 1H), 2.18-2.04(m, 1H), 1.89(td, J ═ 12.3, 6.0Hz, 1H), 1.63(s, 1H), 1.53(s, 5H), 1.49-1.43(m, 12H), 1.38(s, 1H), 1.34(dd, J ═ 9.1, 4.5Hz, 2H), 1.20(t, J ═ 5.5Hz, 3H). ESI-MS M/z calculated 271.21475, Experimental 272.2(M +1) ⁺(ii) a Retention time: 1.64min (LC method E).

And 7: 2, 2-dimethyl-4- (3-methylsulfonyloxybutyl) pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of 4- (3-hydroxybutyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (346mg, 1.275mmol) and triethylamine (1.2mL, 8.6mmol) in dichloromethane (6mL) cooled to 0 ℃ methanesulfonyl chloride (350 μ L, 4.52mmol) was added dropwise. The reaction mixture was stirred for 20h and after 1h was allowed to warm to room temperature (clear solution turned cloudy orange after 10 min). The reaction mixture was quenched with ice water and dichloromethane, then brine, the aqueous layer was further extracted with dichloromethane (2X 20mL) and the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure, the resulting material was dried in vacuo for 1h to give tert-butyl 2, 2-dimethyl-4- (3-methylsulfonyloxybutyl) pyrrolidine-1-carboxylate (440mg, 99%) as a yellow oil (calculated ESI-MS M/z 349.1923, Experimental 350.1(M +1)⁺(ii) a Retention time: 1.8min (LC method E).

And 8: 4- (3-Aminobutyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

Tert-butyl 2, 2-dimethyl-4- (3-methylsulfonyloxybutyl) pyrrolidine-1-carboxylate (440mg, 1.259mmol) was dissolved in a mixture of dioxane (10mL) and ammonium hydroxide (10mL, 30% weight/volume, 85.60mmol) the mixture was heated to 50 ℃ in a sealed vessel for 72 h. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo the crude material was purified by silica gel chromatography (24 g column) using a dichloromethane-methanol gradient (containing 5 mL/L30% ammonium hydroxide) from 0 to 15% methanol to give tert-butyl 4- (3-aminobutyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate as a light yellow oil (199mg, 58%). ¹H NMR (400MHz, dimethyl sulfoxide) 7.86(s, 2H), 3.62-3.49(m, 1H), 3.14(dt, J ═ 17.3, 5.3Hz, 1H), 2.79(dd, J ═ 19.2, 10.2Hz, 1H), 2.08-1.97(m, 1H), 1.93-1.81(m, 1H), 1.56(ddd, J ═ 25.3, 14.2, 6.6Hz, 1H), 1.49-1.43 (m, 1H), 1.42-1.33(m, 15H), 1.24(d, J ═ 5.9Hz, 4H), 1.16(d, J ═ 6.5Hz, 2H).

And step 9: 2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino ] butyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

In a sealed 20mL microwave vial, a solution of 6-fluoropyridine-2-sulfonamide (526mg, 2.986 mmol), tert-butyl 4- (3-aminobutyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (800mg, 2.958mmol), and diisopropylethylamine (2.6mL, 14.93mmol) in dimethyl sulfoxide (8mL) was stirred at 130 ℃ for 16h. The organic extracts were dried over sodium sulfate, evaporated and purified by silica gel chromatography using a 12g column (gradient of 0-85% ethyl acetate in hexane) to give 2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino]Butyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (490mg, 38%).¹H NMR (400MHz, dimethylsulfoxide-d) ₆)7.49(dd，J＝8.4，7.3Hz，1H)， 7.03(s，2H)，6.93(d，J＝7.2Hz，1H)，6.78(d，J＝8.1Hz，1H)，6.59(d, J ═ 8.4Hz, 1H), 4.02(s, 1H), 3.53(d, J ═ 10.0Hz, 1H), 2.78(dd, J ═ 18.9, 10.6Hz, 1H), 2.02(d, J ═ 27.8Hz, 1H), 1.88(s, 1H), 1.55-1.42(M, 2H), 1.42-1.29(M, 16H), 1.23(s, 3H), 1.11(d, J ═ 6.4Hz, 3H), ESI-MS M/z calculated 426.23007, experimental 427.1(M +1)⁺(ii) a Retention time: 0.66min (LC method A).

Step 10: 4- [3- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] butyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (160mg, 0.4258mmol) and carbonyldiimidazole (69mg, 0.4255mmol) were combined in tetrahydrofuran (2.5mL) and stirred at 50 ℃ for 120 min. Followed by addition of 2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino]Butyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (145mg, 0.3399mmol) was added followed by 1, 8-diazabicyclo [5.4.0]Undec-7-ene (110. mu.L, 0.7356mmol) and the reaction was heated at 50 ℃ for 18 h. The reaction was diluted with ethyl acetate and washed with 1M citric acid solution followed by brine. The organics were separated, dried over sodium sulfate, filtered and evaporated, and then purified by reverse phase preparative reverse phase HPLC using C ₁₈Column and method 30-99A1-B1 (acetonitrile-water +5mM hydrochloric acid) purification to give 4- [3- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Butyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (97mg, 36%). ESI-MS calculated M/z 783.27924, Experimental 784.2(M +1)⁺(ii) a Retention time: 2.44min (LC method E).

Step 11: 12, 12, 17-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5(10)6, 8, 19, 21-hexaen-2, 2, 4-trione (diastereomer pair 1) (Compound 35), 12, 17-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (diastereomer pair 2) (compound 36), 12, 17-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (diastereomer pair 1, enantiomer 1) (compound 58), 12, 17-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (diastereomer pair 1, enantiomer 2) (compound 59), 12, 17-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (diastereomer pair 2, enantiomer 1) (compound 60) and 12, 12, 17-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (diastereomer pair 2, enantiomer 2) (compound 61)

Part A: 4- [3- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] butyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (97 mg, 0.1237mmol) was dissolved in dichloromethane (2.0mL), and hydrochloric acid (4M in dioxane) (1000 μ L, 4M, 4.000mmol) was added to the mixture and stirred at room temperature for 3h, the mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate, followed by addition of 2M aqueous sodium carbonate (5mL) to a pH of about 10, the organic layer was extracted with ethyl acetate (2 × 10mL), washed with brine, then dried over sodium sulfate, filtered, and evaporated to dryness under reduced pressure.

And part B: the material from part A was combined with potassium carbonate (90mg, 0.6512mmol), cesium fluoride (30 mg, 0.1975mmol),

Molecular sieves and dimethylsulfoxide (2.0mL) were combined in a vial, purged with nitrogen, capped, heated at 150 ℃ and stirred for 18 h. Cooled to room temperature, the reaction mixture was filtered and then subjected to reverse phase preparative chromatography (C)₁₈Column, 20% to 99% acetonitrile (no modifier)/water (5mM hydrochloric acid)) to give 12, 12, 17-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl-8 ] as an off-white solid as the first diastereomer pair of the enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (diastereomer pair 1) (compound 35) (9.0mg, 22%);¹h NMR (400MHz, dimethylsulfoxide-d)₆) 12.62(s, 1H), 8.21(d, J ═ 2.8Hz, 1H), 7.80(d, J ═ 8.2Hz, 1H), 7.57(dd, J ═ 8.5, 7.2Hz, 1H), 7.05(d, J ═ 7.2Hz, 1H), 6.97(d, J ═ 9.2Hz, 1H), 6.91(d, J ═ 8.2Hz, 1H), 6.68(d, J ═ 8.5Hz, 1H), 6.11(d, J ═ 2.8Hz, 1H), 4.31(t, J ═ 7.2Hz, 2H), 4.17(s, 1H), 3.10(d, J ═ 9.4, 1H), 2.74-2.66(m, 1H), 2.20-10 (t, 2H), 1.5H), 1H, 3.10(d, J ═ 9.4, 1H), 2.6.6.6.6.6.6.6.6 (d, J ═ 2, 1H, 12 (m, 1H), 2H, 1H, 12, 1H, 12 (m, 1H), 2H, 1H, 2H) 1.04(d, J ═ 6.3Hz, 3H), 0.95(d, J ═ 4.6Hz, 2H), 0.90(d, J ═ 11.1Hz, 2H); ESI-MS M/z calculated 647.2502, Experimental 648.2(M +1) ⁺(ii) a Retention time: 2.25min (LC method E); and a second non-enantiomer as an enantiomer to be eluted12, 12, 17-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as an off-white solid of an enantiomeric pair]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (diastereomer pair 2) (compound 36) (33.6mg, 82%);¹h NMR (400MHz, dimethylsulfoxide-d)₆)12.41(s, 1H), 8.21(d, J ═ 2.7Hz, 1H), 7.65(d, J ═ 7.8Hz, 1H), 7.58(dd, J ═ 8.5, 7.3Hz, 1H), 7.20(dd, J ═ 12.2, 7.3Hz, 2H), 6.89(d, J ═ 8.2Hz, 1H), 6.70(d, J ═ 8.2Hz, 1H), 6.10 (d, J ═ 2.7Hz, 1H), 4.31(t, J ═ 7.0Hz, 2H), 3.65(d, J ═ 5.0Hz, 1H), 3.23-2.97(m, 2H), 2.27(dd, J ═ 10.1, 5.1, 1H), 1H, 14 (dd, 14.8.2H, 1H), 1H, 14 (d, 14H), 2H, 14H), 2H, 14 (d, 14H, 1.15-1.06(m, 1H), 0.97-0.93 (m, 2H), 0.89(d, J ═ 11.4Hz, 2H). ESI-MS M/z calculated 647.2502, Experimental 648.2 (M +1) ⁺(ii) a Retention time: 2.29min (LC method E).

And part C: by SFC chromatography using a ChiralPak AS-H (250X 10mm) column (5 μm particle size) and a 16% acetonitrile/methanol (90: 10)/84% carbon dioxide mobile phase (10mL/min, over 8.0min) [ infusion volume 70 μ L of a 24mg/mL solution in acetonitrile/methanol (90: 10)]P-12, 12, 17-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Chiral separation of tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (diastereomer pair 1) (11.5mg) to give 12, 12, 17-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] ketone as the first enantiomer to be eluted as an off-white solid]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (diastereomer pair 1, enantiomer 1) (compound 58) (2.6mg, 45%; 98% ee)) (ii) a ESI-MS M/z calculated 647.2502, Experimental 648.2(M +1)⁺(ii) a Retention time: 2.25min (LC method E) and 12, 12, 17-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as an off-white solid as the second enantiomer to be eluted ]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (diastereomer pair 1, enantiomer 2) (compound 59) (3.6mg, 62%; > 98% ee); ESI-MS M/z calculated 647.2502, Experimental 648.2(M +1)⁺(ii) a Retention time: 2.25min (LC method E).

And part D: by SFC chromatography using a ChiralPak AS-H (250X 10mm) column (5 μm particle size) and a 16% acetonitrile/methanol (90: 10)/84% carbon dioxide mobile phase (10mL/min, over 8.0min) [ infusion volume 70 μ L of a 24mg/mL solution in acetonitrile/methanol (90: 10)]P-12, 12, 17-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Chiral separation of tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (diastereomer pair 2) (55mg) to give 12, 12, 17-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] 8 as the first enantiomer to be eluted as an off-white solid]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (diastereomer pair 2, enantiomer 1) (compound 60) (17.9mg, 64%, > 98% ee); ESI-MS M/z calculated 647.2502, Experimental 648.2(M +1)⁺(ii) a Retention time: 2.3min (LC method E) and 12, 12, 17-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as an off-white solid as the second enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (diastereomer pair 2, enantiomer 2) (compound 61) (18.1mg, 65%, > 98% ee);¹h NMR (400MHz, dimethylsulfoxide-d)₆)12.40(s, 1H), 8.21(d, J ═ 2.7 Hz, 1H), 7.59(dd, J ═ 20.6, 12.9Hz, 2H), 7.18(d, J ═ 7.2Hz, 2H), 6.89(d, J ═ 8.1Hz, 1H), 6.70(d, J ═ 8.3Hz, 1H), 6.10(d, J ═ 2.6Hz, 1H), 4.31(t, J ═ 7.0Hz, 2H), 3.63(s, 1H), 3.12(d, J ═ 30.7Hz, 2H), 2.28(dd, J ═ 21.3, 12.6Hz, 1H), 2.07(t, J ═ 7.0Hz, 2H), 2.03-1.81(m, 1.7H), 1.3 (d, J ═ 21.3, 12.6Hz, 1H), 1.79 (d, 1.3.3, 1H), 1.3.3, 3, 3.3.3, 3, 3.6H, 1H), 2.07(t, 1H, 1H, 3, 5 (d, 3, 5, 1H), 3, 2H) 0.88(s, 2H), ESI-MS M/z calculated 647.2502, Experimental 648.2(M +1) ⁺(ii) a Retention time: 2.3min (LC method E).

Example 10: preparation of 12, 12-dimethyl-8- {3- [ (2, 2, 3, 3-tetramethylcyclopropyl) methoxy]-1H-pyrazol-1-yl } -2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 42)

Step 1: 3- [ (2, 2, 3, 3-tetramethylcyclopropyl) methoxy ] pyrazole-1-carboxylic acid tert-butyl ester

To a degassed solution of triphenylphosphine (51.28g, 195.5mmol) in toluene (360.0mL) at 0 deg.C under nitrogen was added DIAD (39.53g, 37.86mL, 195.5mmol) dropwise, the mixture was stirred at 0 deg.C for 30 min to give a white slurry. To the mixture was added dropwise (2, 2, 3, 3-tetramethylcyclopropyl) methanol (29.84g, 70% w/w, 162.9mmol) and a solution of tert-butyl 3-hydroxypyrazole-1-carboxylate (30g, 162.9mmol) in toluene (600.0mL) at about 5 ℃ over 2 h. The mixture was allowed to warm to ambient temperature and stirred for 18 h. The mixture was heated to 75 ℃ for 6h and then allowed to coolBut to ambient temperature. The slurry was diluted with heptane (900mL) and stirred at ambient temperature for 3h the slurry was filtered through celite and the precipitate was washed with 100mL heptane 3 times the filtrate was concentrated in vacuo to give a thick yellow oil the crude product was column chromatographed on silica gel 750 g with dichloromethane and eluted with a 0-20% ethyl acetate/hexane gradient. The collected fractions containing the product were concentrated in vacuo to give an off-white solid, i.e., 3- [ (2, 2, 3, 3-tetramethylcyclopropyl) methoxy ]Pyrazole-1-carboxylic acid tert-butyl ester (30.1g, 63%).¹H NMR (400MHz, chloroform-d) 7.82(d, J ═ 3.0Hz, 1H), 5.88 (d, J ═ 2.9Hz, 1H), 4.30(d, J ═ 7.7Hz, 2H), 1.61(s, 9H), 1.12(s, 6H), 1.04(s, 6H), 0.70(t, J ═ 7.8Hz, 1H), ESI-MS M/z calculated 294.19434, experimental 295.0(M +1)⁺(ii) a Retention time: 2.19min (LC method B).

Step 2: 3- [ (2, 2, 3, 3-tetramethylcyclopropyl) methoxy ] -1H-pyrazole

To 3- [ (2, 2, 3, 3-tetramethylcyclopropyl) methoxy group]A solution of tert-butyl pyrazole-1-carboxylate (127g, 431.4mmol) in tetrahydrofuran (317.5mL) and ethanol (635.0mL) was slowly added sodium hydroxide (431.4mL, 2M, 862.8mmol) and the mixture was stirred at room temperature overnight. The organic phase was washed twice with brine (2X 300mL) and the aqueous phase was back-extracted once with methyl tert-butyl ether (250 mL.) the combined organic phases were dried, filtered and evaporated to give 3- [ (2, 2, 3, 3-tetramethylcyclopropyl) methoxy ] as a viscous oil]-1H-pyrazole (75g, 89%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)11.78(s, 1H), 7.48(t, J ═ 2.1 Hz, 1H), 5.65(s, 1H), 4.05(d, J ═ 7.7Hz, 2H), 1.08(s, 6H), 1.00(s, 6H), 0.67(t, J ═ 7.7Hz, 1H). ESI-MS M/z calculated 194.1419, Experimental 195.0(M +1) ⁺(ii) a Retention time: 1.43 min (LC method B).

And step 3: 2, 6-dichloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-3-yl) propylamino ] -2-pyridinyl ] sulfonyl ] pyridine-3-carboxamide

Part A: to a solution of 2, 6-dichloropyridine-3-carboxylic acid (200mg, 1.042mmol) in tetrahydrofuran (5mL) was added bis (imidazol-1-yl) methanone (169.0mg, 1.042mmol) and the reaction mixture was stirred at 50 ℃ for 90min, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (343.9mg, 0.8336mmol) followed by the addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (237.9mg, 233.7 μ L, 1.563mmol) and the reaction heated at 50 ℃ for 18 h. The reaction was diluted with ethyl acetate and washed with a saturated aqueous solution of ammonium chloride followed by brine the organics were separated, dried over sodium sulfate, filtered and evaporated the resulting brown residue was purified by silica gel column chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate to give 4- [3- [ [6- [ (2, 6-dichloropyridine-3-carbonyl) sulfamoyl as an off-white sticky substance]-2-pyridyl]Amino group]Propyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (284mg, 46%). ESI-MS M/z calculated 585.15796, Experimental 586.5(M +1) ⁺(ii) a Retention time: 0.79min (LC method A).

And part B: the material from part A was dissolved in dichloromethane (6mL) and trifluoroacetic acid (1.782g, 1.204mL, 15.63mmol) and stirred at room temperature for 5 hours the solvent was removed and the residue was dissolved in ethyl acetate and the organics were washed with a saturated aqueous solution of sodium bicarbonate followed by brine, the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent removed the material was dried under vacuum overnight to give 2, 6-dichloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-3-yl) propylamino group as an off-white sticky material]-2-pyridyl]Sulfonyl radical]Pyridine-3-carboxamide (233mg, 100%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)9.31(s，1H)， 9.15(s，1H)，8.06(d，J＝8.0Hz，1H)，7.73(d，J＝8.1Hz，1H)，7.62(dd，J＝8.5，7.2 Hz，1H)，7.17(d，J＝7.2Hz，1H)，6.79(d, J ═ 8.5Hz, 1H), 3.34(dq, J ═ 14.6, 5.7Hz, 1H), 3.24(dq, J ═ 6.6, 4.1Hz, 2H), 2.89-2.75(M, 1H), 2.45-2.29(M, 1H), 1.93(dd, J ═ 12.8, 7.7Hz, 1H), 1.60-1.45(M, 3H), 1.43-1.33(M, 5H), 1.29(s, 3H), ESI-MS M/z calculated 485.10553, experimental value 486.5(M +1)⁺(ii) a Retention time: 0.5min (LC method A).

And 4, step 4: 8-chloro-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (hydrochloride) (Compound C)

To 2, 6-dichloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-3-yl) propylamino group]-2-pyridyl]Sulfonyl radical]Pyridine-3-carboxamide (200mg, 0.4112mmol) was added to a solution of dimethyl sulfoxide (5.0mL)

Molecular sieves and the reaction mixture was stirred at room temperature for 10 min. Cesium fluoride (194mg, 1.277mmol) and potassium carbonate (1703mg, 12.32mmol) were then added and the reaction mixture was heated at 140 ℃ overnight. The reaction mixture was filtered through a Whatman filter disc (puradisc 25 TF) and subjected to the reverse phase HPLC-MS method using Luna C sold by Phenomenex₁₈(2) Column (75 × 30mM, 5 μm particle size) (pn: 00C-4252-U0-AX) and purified filtrate over 15.0min of a dual gradient run of 30-99% mobile phase B. mobile phase a ═ water (5mM hydrochloric acid). mobile phase B ═ acetonitrile. flow rate 50mL/min, injection volume 950 μ L, and column temperature 25 ℃ gave 8-chloro-12, 12-dimethyl-2 λ as a white solid⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (hydrochloride) (76 mg, 38%).¹H NMR (400MHz, methanol-d)₄)7.69(d，J＝7.9Hz，1H)，7.54(dd，J＝8.5， 7.3Hz，1H)，7.16(d，J＝7.2Hz，1H)，6.67(d，J＝8.5Hz，1H)，6.56(d，J7.9Hz, 1H), 4.14-3.93(M, 1H), 3.26-3.15(M, 1H), 3.09-2.98(M, 1H), 2.78(t, J ═ 10.0Hz, 1H), 2.19(dd, J ═ 15.6, 5.6Hz, 1H), 1.92-1.77(M, 2H), 1.72-1.60(M, 2H), 1.61(s, 3H), 1.51(s, 3H), 1.49-1.34(M, 2H), ESI-MS M/z calculated 449.12885, experimental value 450.4 (M +1) ⁺(ii) a Retention time: 1.92min (LC method B).

And 5: 12, 12-dimethyl-8- {3- [ (2, 2, 3, 3-tetramethylcyclopropyl) methoxy]-1H-pyrazol-1-yl } -2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 42)

Under nitrogen atmosphere at 0 deg.C to obtain 3- [ (2, 2, 3, 3-tetramethylcyclopropyl) methoxy](ii) -1H-pyrazole (11.98mg, 0.06168mmol) in dimethylsulfoxide (1mL) was added scandium triflate (6.073mg, 0.01234mmol) and sodium hydride (10.2mg, 50% w/w, 0.2125mmol)⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (hydrochloride) (30 mg, 0.06168mmol) and the reaction mixture was heated at 120 ℃ for 16 h. The reaction mixture was cooled to room temperature and quenched with a few drops of water the resulting mixture was filtered through a Whatman filter disc (puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS method using a double gradient run of 50-99% mobile phase B over 15.0min (mobile phase a ═ water (no modifier), mobile phase B ═ acetonitrile) to give 12, 12-dimethyl-8- {3- [ (2, 2, 3, 3-tetramethylcyclopropyl) methoxy group ]-1H-pyrazol-1-yl } -2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 42) (2.6mg, 7%).¹H NMR (400MHz, chloroform-d) 8.19(s, 1H), 8.07(s, 1H), 7.57(s, 2H), 7.51(s, 1H), 6.58(s, 1H)H) 5.96(s, 1H), 4.28(d, J ═ 7.8Hz, 2H), 3.88(brs, 1H), 3.41-3.27(M, 2H), 3.21(brs, 1H), 3.07(brs, 1H), 2.61(brs, 1H), 2.08(brs, 1H), 1.63 (s, 6H), 1.71-1.53(M, 3H), 1.26(brs, 1H), 1.14(d, J ═ 2.5Hz, 6H), 1.07(s, 6H), 0.75(t, J ═ 7.7Hz, 1H), ESI-MS M/z calculated value 607.29407, experimental value 608.5(M +1)⁺(ii) a Retention time: 2.86min (LC method B).

Example 11: preparation of 8- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 43)

Step-1: (1-cyclopropyl-2-methoxy-vinyl) cyclopropane

A5000 mL round-bottom flask was equipped with a mechanical stirrer, a cooling bath as an auxiliary containment, a J-Kem temperature probe, an addition funnel, a water-cooled reflux condenser, and a nitrogen inlet/outlet the vessel was charged with (methoxymethyl) triphenylphosphonium chloride (97.3g, 284mmol) and tetrahydrofuran (375mL) under a nitrogen atmosphere to provide a white suspension. Stirring was started and the pot temperature was recorded as 19 ℃ the vessel was then charged with potassium tert-butoxide (31.85g, 0.2838mol), which was added portionwise as a solid over 10min, resulting in an orange-red solution and allowing the exotherm to go to 21 ℃ the mixture was stirred for a further 30min at room temperature. Dicyclopropyl ketone (dicyclopropyl ketone) (25.0g, 227.0mmol) was charged dropwise over 25min to the addition funnel, which was then added without doping, allowing a gradual exotherm to 35 ℃. the resulting red-orange solution was gradually cooled to room temperature, followed by continued stirring at room temperature for 4 h. The resulting biphasic mixture was transferred to a separatory funnel and And allowed to stand for 5min the aqueous phase was drained, the remaining organics washed with a saturated solution of sodium chloride (375mL), the organics were removed and concentrated under reduced pressure to provide a pale yellow oil still containing some water, the mixture was diluted with ethyl acetate (500mL) and then transferred to a separatory funnel and partitioned with water (150 mL). The organics were removed, dried over sodium sulfate (150g) and then filtered through a glass frit buchner funnel the filtrate was concentrated under reduced pressure to provide a pale yellow oil containing some suspended solids (triphenylphosphine oxide). the mixture was diluted with hexane (500mL) and then filtered through a glass frit buchner funnel with a 40mm silica gel layer the filter cake was washed by displacement with hexane (2 x 500 mL.) the filtrate was concentrated under reduced pressure to provide (1-cyclopropyl-2-methoxy-vinyl) cyclopropane (27g, 0.1953mol, 86% yield) as a clear pale yellow oil the calculated ESI-MS M/z 138.10446, experimental 138.0(M +1)⁺(ii) a Retention time: 1.73min (LC method B).

Step-2: 2, 2-dicyclopropylaldehyde

To a solution of (1-cyclopropyl-2-methoxy-vinyl) cyclopropane (128g, 709.4mmol) in tetrahydrofuran (700 mL) was added aqueous hydrochloric acid (250mL, 3M, 750.0mmol) and the mixture was stirred at ambient temperature for 16h, then at 55 ℃ for 4h, then allowed to cool to ambient temperature over 12 h. The mixture was diluted with 500mL of brine and the aqueous phase was separated. The aqueous phase was extracted with 500mL MTBE and the organic phases were combined. The organic phase was washed with 500mL brine, dried over magnesium sulfate, filtered and concentrated in vacuo the resulting oil was diluted with 250mL MTBE and residual water was removed using a separatory funnel the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to afford 2, 2-dicyclopropylaldehyde as a light orange oil (99.2g, 96%). ¹H NMR (400MHz, chloroform-d) 9.74(d, J ═ 2.9Hz, 1H), 1.06(td, J ═ 8.9, 2.9Hz, 1H), 0.94-0.81(m, 2H), 0.64-0.49(m, 4H), 0.32-0.20(m, 4H).

And step 3: [ (E) -1-cyclopropyl-3-methoxy-allyl ] cyclopropane

A5000 mL round bottom flask was equipped with a mechanical stirrer, heating mantle, J-Kem temperature probe, addition funnel, water-cooled reflux condenser, and nitrogen inlet/outlet. The vessel was charged with (methoxymethyl) triphenyl phosphonium chloride (116.8g, 340.7mmol) and tetrahydrofuran (423mL) under a nitrogen atmosphere to provide a white suspension stirring was started and the pot temperature was recorded as 19 ℃. the vessel was then charged with potassium tert-butoxide (38.22g, 340.6 mmol) which was added portionwise as a solid over 30min (one portion 12.74g was added every 10 min) to give an orange-red solution and allowed to exotherm to 40 ℃. The mixture was stirred at room temperature for a further 30min, at which point the pot temperature was recorded as 36 ℃. The addition funnel was then charged with 2, 2-dicyclopropylaldehyde (47g, 60% w/w, intermixed with triphenylphosphine oxide from the previous step, 227.1mmol), which was then added dropwise over 25min without doping, allowing a gradual exotherm to rise to 47 ℃. the resulting orange-red solution was gradually cooled to room temperature, and then stirring was continued at room temperature for 15h, then the reaction mixture was quenched with cold water (1000mL) (pot temperature 19 ℃) allowing an exotherm to 22 ℃. The mixture was stirred for an additional 10min the resulting biphasic mixture was transferred to a separatory funnel and allowed to stand for 5 min. The organics were removed and the residual aqueous solution was extracted with ethyl acetate (2X 300 mL). The combined organic layers were concentrated under reduced pressure to provide a dark amber oil still containing some water, the mixture was diluted with ethyl acetate (500mL), and then transferred to a separatory funnel and partitioned with water (150mL), the organics were removed, washed with a saturated solution of sodium chloride (200mL), dried over sodium sulfate (200g) and then filtered through a glass frit buchner funnel, the filtrate was concentrated under reduced pressure to provide a light amber oil containing some suspended solids (triphenylphosphine oxide), the mixture was diluted with heptane (500mL), and then allowed to stand at room temperature for 30min. The filtrate was concentrated under reduced pressure to a volume of about 200 mL. The light amber solution was cooled to 0 ℃ in a crushed ice/water cooling bath for 30min, during which time more precipitated And (3) a solid. The suspension was filtered through a glass frit buchner funnel and the filter cake was displacement washed with heptane (2 × 50 mL). The filtrate was concentrated under reduced pressure to give [ (E) -1-cyclopropyl-3-methoxy-allyl]Cyclopropane (30g, 87%).¹H NMR (400MHz, chloroform-d) 6.31(dd, J ═ 12.7, 1.1Hz, 1H), 4.68(dd, J ═ 12.7, 7.6Hz, 1H), 3.51(s, 3H), 0.77(qt, J ═ 8.1, 5.0Hz, 2H), 0.54-0.32 (m, 2H), 0.28-0.12(m, 5H), 0.08(ddd, J ═ 9.3, 5.3, 4.1Hz, 2H).

Step-4: 3, 3-dicyclopropylpropanaldehyde

To [ (E) -1-cyclopropyl-3-methoxy-allyl]To a solution of cyclopropane (141g, 555.7mmol) in tetrahydrofuran (500mL) was added aqueous hydrochloric acid (100mL, 3M, 300.0mmol) and the mixture was warmed to 50 ℃ for 2h. The mixture was cooled to ambient temperature and the tetrahydrofuran was removed in vacuo the residue was diluted with dichloromethane (700mL) and the aqueous phase was separated (small emulsion), the organic phase was washed with 500mL brine, dried over magnesium sulfate and filtered₂(50g, 525.1mmol) and the mixture stirred at ambient temperature for 12h filtered the slurry through celite (the celite was masked and needed to be scraped off) the filtrate was slightly cloudy and the filtrate was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 3, 3-dicyclopropylpropanal (76.8g, 100%), ¹H NMR (400MHz, chloroform-d) 9.83(t, J ═ 2.7Hz, 1H), 2.71-2.39(m, 2H), 0.73(ddt, J ═ 5.5, 4.2, 2.9Hz, 3H), 0.56-0.47(m, 2H), 0.42 (dddd, J ═ 9.2, 7.6, 4.0, 2.6Hz, 2H), 0.28-0.21(m, 2H), 0.11-0.04(m, 2H).

Step-5: 3, 3-dicyclopropylpropan-1-ol

To a slurry of lithium aluminum hydride (10.4g, 266.9mmol) in tetrahydrofuran (500mL) was added dropwiseA solution of 3, 3-dicyclopropylpropanal (76g, 549.9mmol) in tetrahydrofuran (150mL) was added and allowed to reflux slightly. The mixture was stirred at ambient temperature for 2 h. The reaction was cooled with an ice bath and quenched by the slow addition of water (10.4mL, 577.3mmol), followed by aqueous sodium hydroxide (10.4mL, 4M, 41.60mmol), followed by water (31.2mL, 1.732 mol.) the slurry was filtered through celite, washed with tetrahydrofuran and concentrated in vacuo to give 3, 3-dicyclopropyl-1-ol (112g, 73%),¹h NMR (400MHz, chloroform-d) 3.81 (t, J ═ 6.9Hz, 2H), 1.76(q, J ═ 6.9Hz, 2H), 0.63(dtt, J ═ 8.8, 8.0, 5.1Hz, 2H), 0.50-0.34 (m, 4H), 0.27-0.14(m, 3H), 0.14-0.02(m, 2H).

Step-6: 3- (3, 3-Dicyclopropylpropoxy) pyrazole-1-carboxylic acid tert-butyl ester

To 3-hydroxypyrazole-1-carboxylic acid tert-butyl ester (36.5g, 198.2mmol) in tetrahydrofuran (450mL) under nitrogen was added 3, 3-dicyclopropylpropan-1-ol (28.0g, 199.7mmol) and triphenylphosphine (57.0g, 217.3 mmol), DIAD (43.0mL, 218.4mmol) was added dropwise to the mixture, the mixture was gradually allowed to exotherm to 45 deg.C after addition, the mixture was stirred at ambient temperature for 1h, the reaction mixture was diluted with hexane (450mL) and about 50% of the solvent was removed in vacuo to give a slurry, the slurry was filtered using a mesoporous glass frit and the solids were washed with hexane (3X 50mL), the filtrate was concentrated in vacuo to give an amber oil, the crude oil was diluted with dichloromethane and subjected to 750g of silica gel column chromatography, the two major fractions were collected with a gradient of 0% -40% ethyl acetate/hexane, the first fraction contained triphenylphosphine and was chromatographed on a 750g silica gel column, eluting with a gradient of 0% to 25% ethyl acetate/hexanes the product from the second column was combined with the product obtained from the first column to give tert-butyl 3- (3, 3-dicyclopropylpropyloxy) pyrazole-1-carboxylate (39.0g, 64%) as a clear oil. ESI-MS M/z calculated 306.19434, Experimental 307.1(M +1)⁺(ii) a Retention time: 2.26min (LC method B).

Step-7: 3- (3, 3-Dicyclopropylpropoxy) -1H-pyrazole (trifluoroacetate)

A solution of tert-butyl 3- (3, 3-dicyclopropylpropyloxy) pyrazole-1-carboxylate (255mg, 0.8322mmol) and trifluoroacetic acid (325.0. mu.L, 4.218mmol) in dichloromethane (1mL) was stirred for 2.5 h. The volatiles were removed in vacuo to give 3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazole (trifluoroacetate) as a colourless oil (266 mg, 100%) which was used directly in the next reaction. ESI-MS M/z calculated 206.1419, Experimental 207.2 (M +1)⁺(ii) a Retention time: 0.59 min (LC method A).

And 8: 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl ] pyridine-3-carboxylic acid tert-butyl ester

Tert-butyl 2, 6-dichloropyridine-3-carboxylate (220.0mg, 0.8867mmol), 3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazole (trifluoroacetate) (266.0mg, 0.8305mmol), potassium carbonate (230mg, 1.664mmol) and 1, 4-diazabicyclo [2.2.2 mmol) were mixed at room temperature]A mixture of octane (20mg, 0.1783mmol) in dimethylsulfoxide (10mL) was stirred for 15h, the reaction was diluted with water and extracted with ethyl acetate, the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated the residue was purified by silica gel column chromatography using a gradient of 100% hexane to 20% ethyl acetate/hexane to give 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl as a colorless oil ]Pyridine-3-carboxylic acid tert-butyl ester (245mg, 71%). ESI-MS M/z calculated 417.18192, Experimental 418.4(M +1)⁺(ii) a Retention time: 1.28min (LC method J).

And step 9: 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl ] pyridine-3-carboxylic acid

2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl at room temperature]A solution of pyridine-3-carboxylic acid tert-butyl ester (245.0mg, 0.5862mmol) in trifluoroacetic acid (500.0. mu.L, 6.490mmol) and dichloromethane (1.5mL) was stirred for 4 h. The solvent was evaporated and the residue was dissolved twice in tetrahydrofuran and concentrated in vacuo to give 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl as a white solid]Pyridine-3-carboxylic acid (204 mg, 96%) was used directly in the next reaction.¹H NMR (400MHz, methanol-d)₄)8.47-8.32(m, 2H), 7.73(d, J ═ 8.5Hz, 1H), 6.03(d, J ═ 2.9Hz, 1H), 4.45(t, J ═ 6.7Hz, 2H), 1.98 (q, J ═ 7.0Hz, 2H), 0.75-0.64(m, 2H), 0.50-0.39(m, 4H), 0.35-0.26(m, 1H), 0.26-0.19 (m, 2H), 0.15-0.06(m, 2H). ESI-MS M/z calculated 361.11932, Experimental 362.3 (M +1)⁺(ii) a Retention time: 0.8min (LC method A).

Step-10: 4- [3- [ [6- [ [ 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl]To a solution of pyridine-3-carboxylic acid (505.1mg, 1.382mmol) in tetrahydrofuran (5mL) was added carbonyldiimidazole (224.1mg, 1.382mmol) and the mixture was stirred at 50 ℃ for 120 min. Subsequently, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino group is added]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (380mg, 0.9211mmol) in tetrahydrofuran (5mL) followed by the addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (280.4mg, 275.4 μ L, 1.842mmol) and the reaction was heated at 50 ℃ for 16 h. The reaction was diluted with ethyl acetate and washed with a small amount of 1: 1 saturated aqueous ammonium chloride solution/brine, the organics were separated, dried over sodium sulfate, filtered and evaporated, chromatographed on silica gel using 100% dichloromethane to 20%Purification of the resulting brown residue in a gentle gradient of% methanol/dichloromethane afforded 4- [3- [ [6- [ [ 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl ] as a white solid]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (356mg, 51%).¹H NMR (400MHz, chloroform-d) 8.31(d, J ═ 2.9Hz, 1H), 8.02(d, J ═ 8.4Hz, 1H), 7.69 (d, J ═ 8.4Hz, 1H), 7.58-7.50(m, 2H), 6.55(dd, J ═ 7.7, 1.6Hz, 1H), 5.95(d, J ═ 2.9Hz, 1H), 4.92(s, 1H), 4.42(t, J ═ 6.9Hz, 2H), 4.02(dd, J ═ 10.7, 7.3Hz, 1H), 3.64-3.54 (m, 1H), 3.17(t, J ═ 11.7Hz, 1H), 2.88(t, J ═ 10.7, 1H), 2.19(d, J ═ 2.9H, 1H), 3.6.6H, 1H, 6.6H, 6H, 1H, 6H, 1H, 6H, 1H, 6H, 5H, 1H, 6H, 1H, 6H, and 15H, 2H) 0.55-0.40 (M, 4H), 0.33(ddd, J ═ 15.9, 9.0, 6.9Hz, 1H), 0.20(dtd, J ═ 9.5, 4.9, 3.6Hz, 2H), 0.14-0.04(M, 2H), ESI-MS M/calculated z 755.3232, experimental value 756.5(M +1) ⁺(ii) a Retention time: 0.6min (LC method L).

Step-11: 8- [3- (3, 3-Dicyclopropylpropoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 43)

4- [3- [ [6- [ [ 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl ] is reacted at room temperature]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]A solution of tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (350mg, 0.4627 mmol) in dichloromethane (2.917mL) and trifluoroacetic acid (527.6mg, 354.1 μ L, 4.627mmol) was stirred for 4h the solvent was removed in vacuo and the residue was dissolved in ethyl acetate. Washed with 2mL of saturated aqueous sodium bicarbonate solution, and the organic layer was collected and the solvent was removed in vacuo, the material was dissolved in dimethylsulfoxide (17.50mL),and adding

Molecular sieves, cesium fluoride (210.8mg, 1.388mmol) and potassium carbonate (191.8mg, 1.388mmol) and heating the reaction mixture at 130 ℃ overnight the reaction mixture was filtered through a Whatman filter disc (puradisc 25TF) and the filtrate was purified by reverse phase HPLC-MS using a two gradient run of 20% -80% mobile phase B over 15.0min (mobile phase a ═ water (0.05% hydrochloric acid), mobile phase B ═ acetonitrile) to give 8- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl as an off-white solid ]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 43) (158mg, 55%).¹H NMR (400 MHz, chloroform-d) 9.99(s, 1H), 8.19(d, J ═ 2.8Hz, 1H), 8.05(d, J ═ 8.4Hz, 1H), 7.57(t, J ═ 7.8Hz, 1H), 7.50(d, J ═ 7.2Hz, 1H), 7.31-7.19(m, 1H), 6.60(d, J ═ 8.3Hz, 1H), 5.91(d, J ═ 2.8Hz, 1H), 4.43(t, J ═ 6.8Hz, 2H), 3.91(s, 1H), 3.35(t, J ═ 8.7Hz, 1H), 3.18(d, J ═ 13.9, 1H), 3.03(t, J ═ 9.2H), 1.60 (t, J ═ 8.7Hz, 1H), 3.18(d, J ═ 13.9, 1H), 3.03(t, J ═ 9, 2H), 0.7H, 8, 1H, 7H, 1H, 13.3.3.3.3.3.18 (d, 8, 1H), 3.7H, 1H, 13.7H, 1H, 13, 7H, 13.7H, 7H, 13, 1H, 3.7H, 13H, 1H) 0.24-0.16(m, 2H), 0.15-0.06(m, 2H). ESI-MS M/z calculated 619.29407, Experimental 620.4(M +1)⁺(ii) a Retention time: 1.32min (LC method J)

Example 12: preparation of 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -18-oxa-2. lambda⁶-thia-3, 9, 11, 23-tetraazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 1) (compound 48) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -18-oxa-2. lambda⁶-thia-3, 9, 11, 23-tetraazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 2) (compound 49)

Step 1: 2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) oxy ] propyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred solution of 4- (3-hydroxypropyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (257mg, 0.9986mmol) in N, N-dimethylformamide (2.056mL) under a nitrogen atmosphere was added sodium hydride (79.87 mg, 1.997mmol) portionwise (note: gas evolution) and the mixture was stirred at room temperature for 20 min. 6-Fluoropyridine-2-sulfonamide (175.9mg, 0.9986mmol) was then added and the resulting mixture was stirred at room temperature for 2 hours 20 minutes, followed by addition of sodium hydride (23.96mg, 0.9984mmol) (note: gas evolution) and stirring of the resulting mixture for 20 minutes, followed by pouring into 1N citric acid and extraction with ethyl acetate (2X). The organic fractions were combined, dried (sodium sulfate), filtered and concentrated to a clear oil, which was purified by silica gel chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate to give 2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) oxy ]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (275.2mg, 67%). ESI-MS M/z calculated 413.19846, experimental value 414.2(M +1)⁺(ii) a Retention time: 0.69min (LC method A).

Step 2: 4- [3- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] oxy ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

In a 20mL vial, 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (96.86mg, 0.25)78mmol) and carbonyldiimidazole (45.81mg, 0.2825mmol) were combined in tetrahydrofuran (1.53mL) and stirred loose at 50 ℃ for 120min, then 2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) oxy group was added]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (193.8mg, 0.2578 mmol) in tetrahydrofuran (2.04mL) followed by the addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (80.81mg, 79.38 μ L, 0.5308mmol) and the reaction was heated at 50 ℃ for 16 h, the reaction was diluted with ethyl acetate and washed with 1M citric acid solution followed by brine the organics were separated, dried over sodium sulfate, filtered and evaporated, then purified by silica gel chromatography using a gentle gradient of 100% dichloromethane to 20% methanol/dichloromethane. The product fractions were combined and repurified by silica gel chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate to give 4- [3- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] methyl ] ethyl acetate ]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Oxy radical]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (64.7mg, 33%). ESI-MS M/z calculated 770.2476, Experimental value 771.2(M +1)⁺(ii) a Retention time: 0.94min (LC method A).

And step 3: 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-3-yl) propoxy ] -2-pyridinyl ] sulfonyl ] -6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide

Reacting 4- [3- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] group]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Oxy radical]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (132.5mg, 0.1718mmol) was dissolved in dichloromethane (578.2 μ L) and trifluoroacetic acid (898.7 mg, 607.2 μ L, 7.882mmol) was added to the mixture and the mixture was stirred at room temperature for 60 min. The mixture was concentrated to dryness under reduced pressure, dissolved in a saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate and the layers were separated. The organic layer was washed with a small amount of brine and then dried (sulfuric acid)Sodium), filtered and concentrated to a white solid 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-3-yl) propoxy)]-2-pyridyl]Sulfonyl radical ]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (110mg, 95%). ESI-MS M/z calculated 670.1952, Experimental 671.2(M +1)⁺(ii) a Retention time: 0.64min (LC method A).

And 4, step 4: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -18-oxa-2. lambda⁶-thia-3, 9, 11, 23-tetraazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 40)

To 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-3-yl) propoxy group]-2-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]To a solution of pyridine-3-carboxamide (126.6mg, 0.1886mmol) in dimethyl sulfoxide (5.063mL) was added potassium carbonate (130.3mg, 0.9430 mmol), cesium fluoride (34.38mg, 0.2263mmol) and a small amount

The resulting mixture was capped and heated to 150 ℃ for 6.5h, then cooled to room temperature and stirred overnight, then the mixture was heated to 165 ℃ for 90min, then cooled to room temperature, diluted with ethyl acetate, and diluted with NH₄A1: 1 saturated aqueous solution of Cl/1M citric acid was then washed with brine. The organic phase was dried (sodium sulfate), filtered and concentrated to an orange oil which was purified by silica gel chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate (product eluted after reaching 100% ethyl acetate) to give 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl-propyl ] as a white solid ]Ethoxy } -1H-pyrazol-1-yl) -18-oxa-2. lambda⁶-thia-3, 9, 11, 23-tetraazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 40)) (58.2mg, 48%). ESI-MS M/z calculated 634.2185, Experimental 635.2(M +1)⁺(ii) a Retention time: 2.29min (LC method B).

And 5: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -18-oxa-2. lambda⁶-thia-3, 9, 11, 23-tetraazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 1) (compound 48) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -18-oxa-2. lambda⁶-thia-3, 9, 11, 23-tetraazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 2) (compound 49)

Racemic 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl) -8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] was chromatographed by SFC using ChiralPak AS-H (250 × 10mm column, 5 μm particle size) and 25% acetonitrile/methanol (90: 10)/75% carbon dioxide mobile phase (10mL/min over 8.0min) (24 mg/mL solution in acetonitrile/methanol injected at volume ═ 70 μ L) ]Ethoxy } -1H-pyrazol-1-yl) -18-oxa-2. lambda⁶-thia-3, 9, 11, 23-tetraazatetracyclo [17.3.1.111, 14.05, 10]The tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 40) (45.3mg, 0.07052mmol) was subjected to chiral separation to give 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] ketone as the first enantiomer to be eluted as a white solid]Ethoxy } -1H-pyrazol-1-yl) -18-oxa-2. lambda⁶-thia-3, 9, 11, 23-tetraazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 1) (compound 48) (22.20mg, 97%); ESI-MS M/z calculated 634.2185, Experimental 635.0(M +1)⁺(ii) a Retention time: 2.30min (LC method B) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid as the second enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -18-oxa-2. lambda⁶-thia-3, 9, 11, 23-tetraazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 2) (compound 49) (22.33mg, 100%);¹h NMR (400MHz, dimethylsulfoxide-d) ₆)12.81(s, 1H), 8.21(d, J ═ 2.8Hz, 1H), 8.01(t, J ═ 7.9Hz, 1H), 7.86(d, J ═ 8.2Hz, 1H), 7.63(d, J ═ 7.4Hz, 1H), 7.13(d, J ═ 8.4Hz, 1H), 6.93(d, J ═ 8.2Hz, 1H), 6.12(d, J ═ 2.8Hz, 1H), 5.17(t, J ═ 12.1Hz, 1H), 4.32(t, J ═ 7.0Hz, 2H), 4.11 (d, J ═ 6.5Hz, 1H), 3.93(d, J ═ 11.1Hz, 1H), 3.19-3.15(m, 2H, 18.92H, 1H, 3.85 (t, m ═ 2.5H), 3.93(d, 1.1H, 1H), 3.2H, 2H, 3.93 (t, 2H, 1H, 3.0, 3.85 (t, 2H), 3.5H, 1H, 2H, 1H, ESI-MS M/z calculated 634.2185, Experimental 635.1(M +1)⁺(ii) a Retention time: 2.29min (LC method B).

Example 13: preparation of 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11-triazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 53)

Step 1: 2, 2-dimethyl-4- (3-oxopropyl) pyrrolidine-1-carboxylic acid tert-butyl ester

Des-Martin periodinane (9.95g, 23.46mmol) was added to 4- (3-hydroxypropyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (5.20g, 20.20mmol) in anhydrous CH at 0 deg.C (ice-water bath) under nitrogen ₂Cl₂(40 mL) after 15min, the reaction was allowed to warm to ambient temperature and stirring was continued for an additional 2 h. The reaction was diluted with ether (200mL) and allowed to relaxA saturated aqueous solution of sodium bicarbonate (100mL) was slowly added (to slow carbon dioxide evolution). Then 10% sodium thiosulfate (50mL) was added and stirred at ambient temperature for 30 min. The combined organics were washed with brine (100mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude material which was purified by medium pressure silica gel chromatography (330g silica gel column, 5 to 35% ethyl acetate/hexane over 35min) to give the desired tert-butyl 2, 2-dimethyl-4- (3-oxopropyl) pyrrolidine-1-carboxylate (3.96g, 77%) as a clear viscous mass.¹H NMR (400MHz, methanol-d)₄)4.48(t, J ═ 5.4Hz, 1H), 3.66(dd, J ═ 11.2, 6.9Hz, 1H), 2.87(q, J ═ 10.7Hz, 1H), 2.31(t, J ═ 7.6Hz, 1H), 2.22-2.07(m, 1H), 1.95(ddt, J ═ 17.2, 12.1, 6.1Hz, 1H), 1.66(q, J ═ 7.9Hz, 1H), 1.62-1.55(m, 1H), 1.54-1.48(m, 2H), 1.47(s, 4H), 1.43(s, 6H), 1.41(s, 2H), 1.31(s, 3H). ESI-MS M/z calculated 255.18344, Experimental 256.2(M +1) ⁺(ii) a Retention time: 1.57min (LC method B).

Step 2: 4-but-3-ynyl-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 2, 2-dimethyl-4- (3-oxopropyl) pyrrolidine-1-carboxylate (1.33g, 5.208mmol) in methanol (31mL) at 0 ℃ was added potassium carbonate (1.62g, 11.72mmol) followed by dropwise addition of (1-dimethoxyphosphoryl-2-oxo-propylidene) -imino-ammonium (12.5mL, 10% weight/volume, 6.473mmol). after completion of the addition, the mixture was warmed to room temperature and stirred for 4h, the solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution (1 x), the aqueous layer was back-extracted twice with ethyl acetate and the organic layers were combined, dried (sodium sulfate), filtered and concentrated to a clear oil, which was purified by silica gel chromatography using a gradient of 100% hexane to 50% ethyl acetate/hexane, 4-but-3-ynyl-2, 2-dimethyl-pyrrolidine-1-carba as a clear oilTert-butyl ester (1.15g, 88%). ESI-MS M/z calculated 251.18852, Experimental 252.2(M +1)⁺(ii) a Retention time: 1.96min.¹H NMR(400MHz，CDCl₃) 3.82-3.56(m，1H)，2.99-2.80(m，1H)，2.35-2.23(m，1H)，2.21(dd，J＝9.5，4.6 Hz，2H)，1.96(s，1H)，1.95-1.86(m，1H)，1.63-1.55(m，2H)，1.53-1.36(m，13H)， 1.30(t，J＝10.8Hz，3H).

And step 3: 2, 2-dimethyl-4- [4- (3-sulfamoylphenyl) but-3-ynyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

Nitrogen was bubbled through 3-iodobenzenesulfonamide (308.0mg, 1.088mmol), 4-but-3-ynyl-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (156.3mg, 0.6218mmol), Pd (PPh) in a vial₃)₂Cl₂(26.19 mg, 0.03731mmol), cuprous iodide (11.84mg, 0.06218mmol) and N, N-dimethylformamide (1.563mL) for 5min, followed by the addition of N-isopropylpropan-2-amine (69.21mg, 95.86. mu.L, 0.6840 mmol), and the vial was sealed and stirred at 50 ℃ for 2.5h, then cooled to room temperature and stirred overnight, cooled to room temperature and poured into water (200mL), and extracted with dichloromethane (2 x 100mL), the organic layers were combined, washed with water (2 x 100mL), dried (magnesium sulfate), filtered and concentrated to an orange oil, this oil was purified by silica gel chromatography using a gradient of 100% hexane to 100% ethyl acetate to give 2, 2-dimethyl-4- [4- (3-sulfamoylphenyl) but-3-ynyl as a yellow oil.]Pyrrolidine-1-carboxylic acid tert-butyl ester (307.9mg, 92%). ESI-MS M/z calculated 406.19263, Experimental 407.2(M +1)⁺(ii) a Retention time: 0.71min (LC method A).

And 4, step 4: 2, 2-dimethyl-4- [4- (3-sulfamoylphenyl) butyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

To 2, 2-two Methyl-4- [4- (3-sulfamoylphenyl) but-3-ynyl]Pyrrolidine-1-carboxylic acid tert-butyl ester (307.9 mg, 0.5744mmol) to which was added platinum oxide (65.20mg, 0.2871mmol), followed by EtOH (2.188 mL), and nitrogen was bubbled through the mixture for 1min, followed by hydrogen for 5min, then the mixture was capped under a balloon of hydrogen and stirred for 3 h. Purged with nitrogen, celite was added, stirred for 1min, then filtered through a pad of celite. The filtrate was concentrated to an orange oil, 2-dimethyl-4- [4- (3-sulfamoylphenyl) butyl]Pyrrolidine-1-carboxylic acid tert-butyl ester (320.4mg, 82%) which was used directly in the next step ESI-MS calculated value 410.22394, experimental value 411.3(M +1)⁺(ii) a Retention time: 0.73min (LC method A).

And 5: 4- [4- [3- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] phenyl ] butyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

In a 20mL vial, 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (95.96mg, 0.2554mmol) and carbonyldiimidazole (41.41mg, 0.2554mmol) were combined in tetrahydrofuran (1.00mL) and stirred loose lid at 50 ℃ for 120 min. Followed by addition of a solution containing 2, 2-dimethyl-4- [4- (3-sulfamoylphenyl) butyl ]Pyrrolidine-1-carboxylic acid tert-butyl ester (69.9mg, 0.1703mmol) in tetrahydrofuran (1.338mL) followed by the addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (50.93 μ L, 0.3406 mmol) and the reaction was heated at 50 ℃ for 16 h. The reaction was diluted with ethyl acetate and washed with a small amount of 1: 1 saturated aqueous ammonium chloride solution/brine. The organics were separated, dried over sodium sulfate, filtered and evaporated, then purified by silica gel chromatography using a gentle gradient of 100% dichloromethane to 20% methanol/dichloromethane to give 4- [4- [3- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Phenyl radical]Butyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (110.5mg,84%). ESI-MS M/z calculated 767.27313, Experimental 768.2(M +1)⁺(ii) a Retention time: 0.95min (LC method A).

Step 6: 2-chloro-N- [3- [4- (5, 5-dimethylpyrrolidin-3-yl) butyl ] phenyl ] sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide (trifluoroacetate)

4- [4- [3- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] group]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical ]Phenyl radical]Butyl radical]Tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (110.5mg, 0.1438mmol) was dissolved in dichloromethane (482.2 μ L) and trifluoroacetic acid (508.3 μ L, 6.598 mmol) was added to the mixture and stirred at room temperature for 40 min. The mixture was concentrated to dryness under reduced pressure, dissolved in a saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate and the layers were separated. The organic fraction was dried (sodium sulfate), filtered and concentrated to an orange oil, which was filtered and used the reverse phase HPLC-MS method using Luna C sold by Phenomenex₁₈(2) Column (75 × 30mM, 5 μm particle size) (pn: 00C-4252-U0-AX) and purification over 15.0min of a dual gradient run of 1-99% mobile phase B (mobile phase a ═ water (5mM hydrochloric acid), mobile phase B ═ acetonitrile, flow rate 50mL/min, injection volume 950 μ L, and column temperature 25 ℃) afforded 2-chloro-N- [3- [4- (5, 5-dimethylpyrrolidin-3-yl) butyl ] N]Phenyl radical]Sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (trifluoroacetate) (104.5mg, 93%). ESI-MS M/z calculated 667.2207, Experimental 668.2(M +1)⁺(ii) a Retention time: 0.67min (LC method A).

And 7: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11-triazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 53)

To 2-chloro-N- [3- [4- (5, 5-dimethylpyrrolidin-3-yl) butyl]Phenyl radical]Sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]To a solution of pyridine-3-carboxamide trifluoroacetate (112.5mg, 0.1438 mmol) in dimethyl sulfoxide (4.499mL) were added potassium carbonate (119.2mg, 0.8625mmol), cesium fluoride (26.22mg, 0.1726mmol) and a small amount

The resulting mixture was capped and heated to 165 ℃ for 6 h. The mixture was then cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution and brine. The organic phase was dried (sodium sulfate), filtered and concentrated to an orange oil which was purified by silica gel chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate to give 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a yellow solid]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11-triazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 53) (46.5mg, 51%).¹H NMR (400 MHz, dimethylsulfoxide-d)₆)12.44(s, 1H), 8.21(d, J ═ 2.8Hz, 1H), 7.84(s, 1H), 7.81(s, 1H), 7.78-7.74(m, 1H), 7.59(s, 2H), 6.93(d, J ═ 8.2Hz, 1H), 6.12(d, J ═ 2.8Hz, 1H), 4.31(t, J ═ 7.0Hz, 2H), 2.75(s, 3H), 2.65(s, 1H), 2.08(t, J ═ 7.0Hz, 3H), 1.82 (td, J ═ 13.9, 12.7, 6.0Hz, 2H), 1.59(s, 3H), 1.53(s, 1H), 1.51(s, 3H), 1.47(s, 2H), 1.01 (s, 14.7, 6.0Hz, 2H), 1.59(s, 3H), 1.53(s, 1H), 1.51(s, 3H), 1.47(s, 14, 14.0H), 14.0 (m, 3H), 3H, and 3. ESI-MS M/z calculated 631.244, Experimental 632.1(M +1)⁺(ii) a Retention time: 2.44min (LC method B).

Example 14: preparation of 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11-triazatetracyclo [17.2.2.111, 14.05, 10]Tetracosane-1 (21), 5, 7, 9, 19, 22-hexaen-2, 2, 4-trione (enantiomer 1) (compound 54) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11-triazatetracyclo [17.2.2.111, 14.05, 10 ]Tetracosane-1 (21), 5, 7, 9, 19, 22-hexaen-2, 2, 4-trione (enantiomer 2) (compound 55)

Step 1: 2, 2-dimethyl-4- [4- (4-sulfamoylphenyl) but-3-ynyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

Nitrogen was bubbled through 4-bromobenzenesulfonamide (256.9mg, 1.088mmol), 4-but-3-ynyl-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (156.3mg, 0.6218mmol), Pd (PPh) in a vial₃)₂Cl₂(26.19 mg, 0.03731mmol), cuprous iodide (11.84mg, 0.06218mmol) and N, N-dimethylformamide (1.563mL) for 5min, followed by the addition of N-isopropylpropan-2-amine (69.21mg, 95.86. mu.L, 0.6840 mmol), and the vial was sealed and stirred at 50 ℃ for 75min, then cooled to room temperature and stirred overnight, cooled to room temperature and poured into water (200mL), and extracted with dichloromethane (2 x 100mL), the organic layers were combined, washed with water (2 x 100mL), dried (magnesium sulfate), filtered and concentrated to an orange oil, the oil was purified by silica gel chromatography using a gradient of 100% hexane to 100% ethyl acetate to give 2, 2-dimethyl-4- [4- (4-sulfamoylphenyl) but-3-ynyl as a white solid.]Pyrrolidine-1-carboxylic acid tert-butyl ester (192.5mg, 76%). ESI-MS M/z calculated 406.19263, Experimental 407.1(M +1) ⁺(ii) a Retention time: 0.71min (LC method A).

Step 2: 2, 2-dimethyl-4- [4- (4-sulfamoylphenyl) butyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

To 2, 2-dimethyl-4- [4- (4-sulfamoylphenyl) but-3-ynyl]Pyrrolidine-1-carboxylic acid tert-butyl ester (192.5 mg, 0.4735mmol) to which palladium oxide (53.75mg, 0.2367mmol) was added followed by EtOH (1.804 mL) and nitrogen bubbled through the mixture for 1min, followed by hydrogen bubbled through the mixture for 5min, then the mixture was capped under a balloon of hydrogen and stirred for 3h, purged with nitrogen, celite was added, stirring for 1min, then filtered through a pad of celite, the filtrate was concentrated to an off-white solid, 2-dimethyl-4- [4- (4-sulfamoylphenyl) butyl ] 2]Pyrrolidine-1-carboxylic acid tert-butyl ester (179.5mg, 92%). ESI-MS M/z calculated 410.22394, Experimental value 411.2(M +1)⁺(ii) a Retention time: 0.75min (LC method A).

And step 3: 4- [4- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] phenyl ] butyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

In a 20mL vial, 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (164.3mg, 0.4372mmol) and carbonyldiimidazole (77.70mg, 0.4792mmol) were combined in tetrahydrofuran (2.576mL) and stirred loosely at 50 ℃ for 120min, then 2, 2-dimethyl-4- [4- (4-sulfamoylphenyl) butyl ] containing ]Pyrrolidine-1-carboxylic acid tert-butyl ester (179.5mg, 0.4372mmol) in tetrahydrofuran (3.436mL) followed by the addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (137.0mg, 134.6 μ tL, 0.9002mmol) and the reaction was heated at 50 ℃ for 16 h, the reaction was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution followed by brine, the organic layer was dried over sodium sulfate, evaporated, and then using reverse phase HPLC-MS method using Luna C sold by Phenomenex₁₈(2) Column (75X 30 mm, 5 μm particle size) (pn: 00C-4252-U0-AX) and 30-99% flow over 15.0minPurification of phase B was performed in a dual gradient run (mobile phase a ═ water (5mM hydrochloric acid), mobile phase B ═ acetonitrile, flow rate 50mL/min, injection volume 950 μ L, and column temperature 25 ℃). The fractions of the expected product were combined and acetonitrile was removed under reduced pressure. The material was then diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate (1 ×) and brine (1 ×), dried (sodium sulfate), filtered and concentrated to provide 4- [4- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] as a clear oil]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Phenyl radical]Butyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (132.8mg, 40%). ESI-MS M/z calculated 767.27313, Experimental 768.2(M +1) ⁺(ii) a Retention time: 0.96min (LC method A).

And 4, step 4: 2-chloro-N- [4- [4- (5, 5-dimethylpyrrolidin-3-yl) butyl ] phenyl ] sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide

4- [4- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] group]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Phenyl radical]Butyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (132.8mg, 0.1729mmol) was dissolved in dichloromethane (579.5 μ L) and trifluoroacetic acid (904.5mg, 611.1 μ L, 7.933mmol) was added to the mixture and the mixture was stirred at room temperature for 60 min. The mixture was concentrated to dryness under reduced pressure, dissolved in saturated aqueous sodium bicarbonate and ethyl acetate and the layers separated the organic layer (sodium sulfate) was dried, filtered and concentrated to a white solid, 2-chloro-N- [4- [4- (5, 5-dimethylpyrrolidin-3-yl) butyl]Phenyl radical]Sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (99.8mg, 86%). ESI-MS M/z calculated 667.2207, Experimental 668.3(M +1)⁺(ii) a Retention time: 0.66min (LC method A).

And 5: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -2 lambda ⁶-thia-3, 9, 11-triazatetracyclo [17.2.2.111, 14.05，10]Tetracosan-1 (21), 5, 7, 9, 19, 22-hexaen-2, 2, 4-trione (compound 52)

To 2-chloro-N- [4- [4- (5, 5-dimethylpyrrolidin-3-yl) butyl]Phenyl radical]Sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]To a solution of pyridine-3-carboxamide (99.8mg, 0.1494mmol) in dimethyl sulfoxide (3.991mL) were added potassium carbonate (103.2mg, 0.7470mmol), cesium fluoride (27.24mg, 0.1793mmol) and a small amount

The resulting mixture was capped and heated to 155 ℃ overnight. The organic phase was dried (sodium sulfate), filtered and concentrated to an orange oil which was purified by silica gel chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate to give 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11-triazatetracyclo [17.2.2.111, 14.05, 10]Tetracosan-1 (21), 5, 7, 9, 19, 22-hexaen-2, 2, 4-trione (compound 51) (25 mg, 26%).¹H NMR (400MHz, dimethylsulfoxide-d) ₆)12.21(s, 1H), 8.17(d, J ═ 2.8Hz, 1H), 8.07(d, J ═ 7.8Hz, 1H), 7.86(d, J ═ 8.3Hz, 1H), 7.76(d, J ═ 8.0Hz, 1H), 7.46(d, J ═ 16.6Hz, 2H), 6.89(d, J ═ 8.3Hz, 1H), 6.10(d, J ═ 2.8Hz, 1H), 4.31(t, J ═ 7.0Hz, 2H), 2.92-2.80(m, 1H), 2.74(dt, J ═ 13.9, 6.9Hz, 1H), 2.19(s, 1H), 2.07(t, J ═ 7.1, 2H), 1.94 (d, J ═ 13.85, 6.9Hz, 1H), 1H, 2.19(s, 1H), 2.07(t, J ═ 7.1H, 2.1H), 1H, 6.85 (1H), 1H, 5 (1H), 6.8H, 1H, 2H) 0.89(d, J ═ 10.8Hz, 2H), 0.77(q, J ═ 11.6Hz, 1H), 0.36(s, 1H). ESI-MS M/z calculated 631.244, Experimental 632.1(M +1)⁺(ii) a Retention time: 246min (LC method B).

Step 6: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11-triazatetracyclo [17.2.2.111, 14.05, 10]Tetracosane-1 (21), 5, 7, 9, 19, 22-hexaen-2, 2, 4-trione (enantiomer 1) (compound 54) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11-triazatetracyclo [17.2.2.111, 14.05, 10 ]Tetracosane-1 (21), 5, 7, 9, 19, 22-hexaen-2, 2, 4-trione (enantiomer 2) (compound 55)

Racemic 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl) 8 was chromatographed by SFC using ChiralPak AS-H (250 × 10mm column, 5 μm particle size) and 25% acetonitrile/methanol (90: 10)/75% carbon dioxide mobile phase (10mL/min over 6.0min) (70 μ L injection volume of 24mg/mL solution in 85% acetonitrile/methanol (90: 10)/15% dimethylsulfoxide)]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11-triazatetracyclo [17.2.2.111, 14.05, 10]The tetracosane-1 (21), 5, 7, 9, 19, 22-hexaen-2, 2, 4-trione (21.9mg, 0.03411mmol) was subjected to chiral separation to give 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] ketone as the first enantiomer to be eluted as a white solid]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11-triazatetracyclo [17.2.2.111, 14.05, 10]Tetracosan-1 (21), 5, 7, 9, 19, 22-hexaen-2, 2, 4-trione (enantiomer 1) (compound 54) (10.01mg, 92%); ESI-MS M/z calculated 631.244, Experimental 632.2(M +1)⁺(ii) a Retention time: 2.44min (LC method B), and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid of the second enantiomer to be eluted ]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11-triazatetracyclo [17.2.2.111, 14.05, 10]Tetracosane-1 (21), 5, 7, 9, 19, 22-hexaen-2, 2, 4-trione (enantiomer 2) (esterification)Compound 55) (8.59mg, 80%);¹h NMR (400MHz, dimethylsulfoxide-d)₆)12.20(s, 1H), 8.17(d, J ═ 2.8Hz, 1H), 8.07(dd, J ═ 8.0, 2.1Hz, 1H), 7.86(d, J ═ 8.3Hz, 1H), 7.76(dd, J ═ 8.1, 2.0Hz, 1H), 7.49(d, J ═ 8.2Hz, 1H), 7.44(d, J ═ 8.2Hz, 1H), 6.90(d, J ═ 8.3Hz, 1H), 6.10(d, J ═ 2.7Hz, 1H), 4.31(t, J ═ 7.0Hz, 2H), 2.87(dt, J ═ 13.4, 6.4, 1H), 2.74(dt, J ═ 14.0, 7.0, 1.0, 7.0Hz, 1H), 2.5 (d, J ═ 8.8, 1H), 1H), 6.9 (d, J ═ 8.5H, 1H), 4 (1H), 4, 1H), 4 (1H, 4, 1H), 4H), 4 (1H), 6.9 (d, 8.5H, 1H), 1.39(t, J ═ 12.3Hz, 2H), 1.02(dt, J ═ 12.8, 6.5Hz, 1H), 0.96(td, J ═ 4.9, 4.4, 3.1Hz, 2H), 0.91-0.85(M, 2H), 0.77(q, J ═ 10.7Hz, 1H), 0.36(s, 1H), ESI-MS M/z calculated 631.244, experimental 632.2(M +1)⁺(ii) a Retention time: 2.44min (LC method B).

Example 15: preparation of 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11-triazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 1) (compound 56) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11-triazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 2) (compound 57)

Step 1: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11-triazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 1) (compound 56) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11-triazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 2) (compound 57)

Racemic 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl) 12, 12-dimethyl-8 using ChiralPak AS-H (250 × 10mm column, 5 μm particle size) and 25% acetonitrile/methanol (90: 10)/75% carbon dioxide mobile phase (10mL/min over 8.0min) (70 μ L injection volume of 24mg/mL solution in 85% acetonitrile/methanol (90: 10)/15% dimethylsulfoxide) by SFC chromatography ]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11-triazatetracyclo [17.3.1.111, 14.05, 10]The tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (41.7 mg, 0.06575mmol) was subjected to chiral separation to give 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] ketone as the first enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11-triazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 1) (compound 56) (20.2mg, 97%); ESI-MS M/z calculated 631.244, Experimental 632.2(M +1)⁺(ii) a Retention time: 2.44min (LC method B) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as the second enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11-triazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 2) (compound 57) (15.9mg, 75%);¹h NMR (400MHz, dimethylsulfoxide-d)₆)12.44(s，1H)，8.21(d，J＝2.8Hz，1H)，7.87-7.75(m，3H)，7.63-7.57(m， 2H)，6.93(dd，J＝8.2，1.2Hz，1H)，6.12(dd，J＝2.8，0.9Hz，1H)，4.31(t，J＝7.0Hz， 2H)，2.75(d，J＝6.0Hz，2H)，2.68-2.62(m，1H)，2.11-2.05(m，3H)，1.83(dt，J＝ 12.6，6.3Hz，2H)，1.58(s，3H)，1.51(s，6H)，1.15(t，J＝8.9Hz，1H)，0.97(d, J ═ 3.4 Hz, 1H), 0.97-0.95(m, 2H), 0.91(s, 1H), 0.90(s, 2H), 0.72(s, 1H). ESI-MS M/z calculated 631.244, Experimental 632.2(M +1) ⁺(ii) a Retention time: 2.43min (LC method B).

Example 16: preparation of 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 20, 25-pentaazatetracyclo [19.3.1.111, 14.05, 10]Hexacosane-1 (24), 5, 7, 9, 21(25), 22-hexaen-2, 2, 4-trione (enantiomer 1) (compound 63) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 20, 25-pentaazatetracyclo [19.3.1.111, 14.05, 10]Hexacosane-1 (24), 5, 7, 9, 21(25), 22-hexaen-2, 2, 4-trione (enantiomer 2) (compound 64)

Step 1: 1- (bromomethyl) -2-oxo-cyclohexanecarboxylic acid ethyl ester

A solution of ethyl 2-cyclohexanone formate (84.0g, 493mmol) in tetrahydrofuran (350mL) was added dropwise over a four hour period to a slurry of 60% sodium hydride (25.7g, 641mmol) and hexamethylphosphoramide (112mL, 641mmol) in tetrahydrofuran (850mL), and the resulting mixture was stirred at room temperature for one hour. Dibromomethane (173mL, 2470mmol) was then added dropwise over a period of one hour, and the mixture was refluxed at 70 ℃ for 16 h. The reaction mixture was diluted with diethyl ether (6L) and the organic layer was washed with water (5 x 850mL), the aqueous phase was discarded, and the organic phase was dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography using a 0-15% hexane/ethyl acetate gradient to give ethyl 1- (bromomethyl) -2-oxo-cyclohexanecarboxylate (68g, 52%) as a clear oil. Purity is obtained by ¹H NMR was determined to be about 80%.¹H NMR(250MHz， CDCl₃)4.35-4.15(m, 2H), 3.88-3.50(dd, 2H), 2.75-2.64(dd, 1H), 2.49-2.41(m, 2H), 2.30-2.17(p, 2H), 2.10-1.75(m, 2H), 1.74-1.53(m, 2H), 1.32-1.22(m, 3H). The crude material was used in the next step without further purification.

Step 2: 2-Methylenepimelic acid diethyl ester

A slurry of ethyl 1- (bromomethyl) -2-oxo-cyclohexanecarboxylate (68g, 258mmol) and potassium carbonate (71.4 g, 517mmol) in ethanol (600mL) was stirred at room temperature for 16h.¹H NMR(250MHz，CDCl₃) 6.17(s, 1H), 5.54(s, 1H), 4.23-4.06(m, 4H), 2.35-2.15(t, 4H), 1.73-1.40(m, 4H), 1.29-1.07(m, 6H). ESI-MS M/z calculated 228.29, Experimental 229.0(M +1)⁺. Retention time: 4.97min (LC method Q).

And step 3: 2- (2-methyl-2-nitro-propyl) pimelic acid diethyl ester

Diethyl 2-methylenepimelate (48.6g, 213mmol), 2-nitropropane (58mL, 639mmol) and 1, 8-diazabicyclo [5.4.0 ] were reacted at 85 deg.C]A mixture of undec-7-ene (3.2mL, 21mmol) was heated for five hours the mixture was concentrated and purified by silica gel chromatography using a 0-15% hexane/ethyl acetate gradient to give diethyl 2- (2-methyl-2-nitro-propyl) pimelate (58g, 85%) as a clear oil. ESI-MS M/z calculated 317.38, Experimental 318.1(M +1) ⁺. Retention time: 5.19min (LC method Q).

And 4, step 4: 5- (5, 5-dimethyl-2-oxo-pyrrolidin-3-yl) pentanoic acid ethyl ester

To a solution of diethyl 2- (2-methyl-2-nitro-propyl) pimelate (19g, 59.8mmol) in ethanol (400mL) was added raney nickel slurry (9g) and the resulting mixture was heated to 80 ℃ in a bayer reactor under 2 bar of hydrogen for 22h. celite (50g) was added to the reactor and the mixture was filtered the solids were discarded and the filtrate was concentrated in vacuo to obtain ethyl 5- (5, 5-dimethyl-2-oxo-pyrrolidin-3-yl) pentanoate as a light colored oil (13.2g, 91% yield). ESI-MS M/z calculated 241.33, experimental 242.1 (M +1)⁺Retention time: 3.79min (LC method Q). the crude product was used in the next step without further purification.

And 5: 5- (5, 5-dimethylpyrrolidin-3-yl) pentan-1-ol

To a solution of ethyl 5- (5, 5-dimethyl-2-oxo-pyrrolidin-3-yl) pentanoate (13.2g, 54.7mmol) in tetrahydrofuran (200mL) was added lithium aluminum hydride (6.2g, 164.1mmol) portionwise, followed by refluxing the resulting slurry under nitrogen atmosphere for 17h, carefully quenching the mixture with saturated aqueous sodium sulfate (50mL) and filtering. The solid was discarded and the aqueous phase was separated and discarded. The organic phase was concentrated to give 5- (5, 5-dimethylpyrrolidin-3-yl) -pentan-1-ol (8.8g) as a pale yellow oil, calculated ESI-MS M/z 185.31, experimental 186.3 (M +1) ⁺. Retention time: 1.98min (LC method Q). The crude product was used in the next step without further purification.

Step 6: 4- (5-hydroxypentyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To 5- (5, 5-dimethylpyrrolidin-3-yl) -pentan-1-ol (27.0g, 145.7 mm)ol) to a solution in dichloromethane (200 mL) was added a solution of sodium bicarbonate (24.5g, 291.4mmol) in water (150mL), followed by di-tert-butyl dicarbonate (31.8g, 145.7mmol). The phases were separated and the aqueous phase was discarded. The organic phase was concentrated in vacuo and purified by silica gel chromatography using a 0-45% hexane/ethyl acetate gradient to give tert-butyl 4- (5-hydroxypentyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (32.0g, 77%) as a clear oil.¹H NMR(250MHz，CDCl₃)4.29(q, 1H), 3.53(s, 1H), 3.37(q, 2H), 2.75(q, 1H), 2.05(s, 2H), 1.87(M, 1H), 1.43-1.17(M, 23H). ESI-MS M/z Calculations 285.43, Experimental 286.4(M +1)⁺Retention time: 5.20min (LC method Q).

And 7: 2, 2-dimethyl-4- (5-methylsulfonyloxypentyl) pyrrolidine-1-carboxylic acid tert-butyl ester

A solution of tert-butyl 4- (5-hydroxypentyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (10.5g, 36.8 mmol) and triethylamine (10.3mL, 73.6mmol) in dichloromethane (100mL) was cooled in an ice-water bath, followed by dropwise addition of methanesulfonyl chloride (3.2mL, 40.5mmol) over a 15 min period, and the resulting mixture was stirred in an ice bath for one hour. Quench the reaction with a saturated solution of sodium bicarbonate (50 mL.) the aqueous phase is discarded and the organic phase is concentrated to give tert-butyl 2, 2-dimethyl 4- (5-methylsulfonyloxypentyl) pyrrolidine-1-carboxylate (13.3g, 99%) as a yellow oil-ESI-MS M/z calculated 363.16, Experimental 364.3(M +1) ⁺Retention time: 5.77min crude product was used in the next step without further purification (LC method Q).

And 8: 4- (5-Aminopentyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2, 2-dimethyl-4- (5-methyl) is reacted at 50 DEG CSulfonyloxypentyl) pyrrolidine-1-carboxylic acid tert-butyl ester (13.3 g, 36.6mmol) in tetrahydrofuran (275mL) and 28% aqueous ammonium hydroxide (275mL) was stirred for 24 h. Tetrahydrofuran and ammonia were removed in vacuo and the remaining aqueous phase was extracted with dichloromethane (3 × 100mL) and the combined organics were concentrated to an oil and purified by silica gel chromatography using a 0-15% dichloromethane/methanol (0.25% ammonium hydroxide) gradient to give tert-butyl 4- (5-aminopentyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (5.4g, 52%) as a light colored oil.¹H NMR(250MHz，CDCl₃)3.53(q, 1H), 2.75(q, 1H), 2.05(s, 2H), 1.86(M, 1H), 1.43-1.10(M, 23H). ESI-MS M/z calculated 284.45, experimental 285.4(M +1)⁺. Retention time: 4.07min (LC method Q).

And step 9: 2, 2-dimethyl-4- [5- [ (6-sulfamoyl-2-pyridyl) amino ] pentyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

A 100mL round bottom flask was charged with tert-butyl 4- (5-aminopentyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (1.028g, 3.614mmol), 6-fluoropyridine-2-sulfonamide (636mg, 3.610mmol) and anhydrous dimethylsulfoxide (10mL), potassium carbonate (519mg, 3.755mmol) was added (just milled in a mortar), and the mixture was stirred at 100 ℃ for 20h. After drying over sodium sulfate and evaporation, the residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (0 to 100% over 30 min)/hexane, the pure fractions were collected and the solvent was evaporated to give 2, 2-dimethyl-4- [5- [ (6-sulfamoyl-2-pyridyl) amino as a white solid foam ]Pentyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (1.184g, 74%). ESI-MS M/z calculated 440.24573, Experimental value 441.3 (M +1)⁺(ii) a Retention time: 1.86min (LC method B).

Step 10: 4- [5- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] pentyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

In a 20mL vial, 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (19.8mg, 0.8511mmol) and carbonyldiimidazole (138.0mg, 0.8511mmol) were combined in tetrahydrofuran (3.588mL) and stirred loose lid at 50 ℃ for 120 min. Followed by addition of a solution containing 2, 2-dimethyl-4- [5- [ (6-sulfamoyl-2-pyridyl) amino group]Pentyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (250mg, 0.5674 mmol) in tetrahydrofuran (4.785mL) followed by the addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (169.7 μ L, 1.135mmol) and the reaction heated at 50 ℃ for 16 h the reaction was diluted with ethyl acetate and washed with a saturated aqueous solution of ammonium chloride followed by brine the organics were separated, dried over sodium sulfate, filtered and evaporated followed by silica gel chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate to give 4- [5- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] methyl ] propyl ] 4- [5- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] methyl ] acetate ]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Pentyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (416.8mg, 92%). ESI-MS M/z calculated 797.2949, Experimental 798.3(M +1)⁺(ii) a Retention time: 0.92 min (LC method A).

Step 11: 2-chloro-N- [ [6- [5- (5, 5-dimethylpyrrolidin-3-yl) pentylamino ] -2-pyridinyl ] sulfonyl ] -6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide

Reacting 4- [5- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] group]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Pentyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (416.8mg, 0.5221mmol) is dissolved inDichloromethane (1.189mL) and trifluoroacetic acid (1.845 mL, 23.95mmol) was added to the mixture and the mixture was stirred at room temperature for 60 min. The mixture was concentrated to dryness under reduced pressure, dissolved in a saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate and the layers were separated. The organic layer was dried (sodium sulfate), filtered and concentrated to a white solid, 2-chloro-N- [ [6- [5- (5, 5-dimethylpyrrolidin-3-yl) pentylamino]-2-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (361mg, 91%). ESI-MS M/z calculated 697.2425, Experimental 698.2(M +1)⁺(ii) a Retention time: 0.64min (LC method A).

Step 12: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 20, 25-pentaazatetracyclo [19.3.1.111, 14.05, 10]Hexacosane-1 (24), 5, 7, 9, 21(25), 22-hexaen-2, 2, 4-trione (enantiomer 1) (compound 63) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 20, 25-pentaazatetracyclo [19.3.1.111, 14.05, 10]Hexacosane-1 (24), 5, 7, 9, 21(25), 22-hexaen-2, 2, 4-trione (enantiomer 2) (compound 64)

To 2-chloro-N- [ [6- [5- (5, 5-dimethylpyrrolidin-3-yl) pentylamino group]-2-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]To a solution of pyridine-3-carboxamide (361mg, 0.4736 mmol) in dimethyl sulfoxide (13.22mL) were added potassium carbonate (392.6mg, 2.841mmol), cesium fluoride (86.33mg, 0.5683mmol) and a small amount

The resulting mixture was capped and heated to 165 ℃ for 16h, then the mixture was cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution and brine. The organic phase was dried (sodium sulfate), filtered and concentrated to 42 2mg of brown amorphous solid, chromatographed by SFC using LUX 3 (250X 21mM column, 5 μm particle size) and 60% methanol (20mM NH)₃Additive)/40% carbon dioxide mobile phase (30mL/min) to chiral separation of the solid to give 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid as the first enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 20, 25-pentaazatetracyclo [19.3.1.111, 14.05, 10]Hexacosane-1 (24), 5, 7, 9, 21(25), 22-hexaen-2, 2, 4-trione (enantiomer 1) (compound 63) (74.4mg, 47%);¹h NMR (400MHz, dimethylsulfoxide-d)₆)12.69(bs, 1H), 8.19(d, J ═ 2.7Hz, 1H), 7.78(d, J ═ 8.2Hz, 1H), 7.48(s, 1H), 7.08(d, J ═ 6.9Hz, 2H), 6.85(d, J ═ 8.0Hz, 1H), 6.58(s, 1H), 6.07(d, J ═ 2.6Hz, 1H), 4.31(t, J ═ 7.0Hz, 2H), 3.84(d, J ═ 14.2Hz, 1H), 3.06(s, 1H), 2.89(s, 1H), 2.79(s, 1H), 2.08(t, J ═ 7.1 Hz, 3H), 1.81(dd, J ═ 11.6, 5.4, 1H), 1.01(s, 1H), 2.93 (d, 1H), 2.0.47H), 3.93 (d, 3.0, 3.8H), 3.1H, 3.47 (d, 3.0H), 3.47 (d, 3.8 (d, 1H), 3.0H), ESI-MS M/z calculated 661.2658, Experimental 662.2(M +1) ⁺(ii) a Retention time: 2.29min (LC method B), and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid of the second enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 20, 25-pentaazatetracyclo [19.3.1.111, 14.05, 10]Tetracosan-1 (24), 5, 7, 9, 21(25), 22-hexaen-2, 2, 4-trione (enantiomer 2) (compound 64) (79.2mg, 50%);¹h NMR (400MHz, dimethylsulfoxide-d)₆)12.50(s，1H)，8.21(d，J＝2.8Hz，1H)，7.82(d，J＝8.2Hz，1H)，7.56(s， 1H)，7.14(s，1H)，6.91(d，J＝7.8Hz，2H)，6.70(s，1H)，6.11(s，1H)，4.31(t，J＝7.0 Hz，2H)，3.88(s，1H)，3.06(s，1H)，2.74(s，1H)，2.62(d，J＝32.1Hz，1H)，2.08(t，J＝ 7.1Hz，2H)，1.83(dd，J＝11.8，5.3Hz，1H)，1.67-1.57(m，1H)，1.55(d，J＝10.5Hz，6H)，1.48(t，J＝12.1Hz，3H)，1.30(s，2H)，1.23(s，1H)，1.01(d, J ═ 9.5Hz, 1H), 0.98-0.95(M, 2H), 0.95-0.87(M, 3H), ESI-MS M/z calculated 661.2658, experimental 662.2 (M +1)⁺(ii) a Retention time: 2.29min (LC method B).

Example 17: preparation of (14S) -8- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 66)

Step 1: (4S) -2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino ] propyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

Racemic 2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino was chromatographed by SFC using ChiralPak IG (250 × 21.2mm column, 5 μm particle size) and 40% methanol/60% carbon dioxide mobile phase (70mL/min over 11.0min) (injection volume of 500 μ L of 32 mg/mL solution in methanol) ]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (7g, 16.97mmol) was subjected to chiral separation to give (4S) -2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino group as the first peak to be eluted]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (3.4481g, 99%). ESI-MS M/z calculated 412.21442, experimental 413.2(M +1)⁺(ii) a Retention time: 0.63min (LC method A).

Step 2: (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

Part A: to 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl ] pyridine-3-carboxylic acid (8.9g, 24.60mmol) in tetrahydrofuran (80mL) was slowly added carbonyldiimidazole (4.4g, 27.14mmol) and the mixture was stirred at ambient temperature for 1 hour.

And part B: to a solution containing (4S) -2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino group]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (10.1g, 24.48mmol) was added to tetrahydrofuran (40mL) to which was added 2, 3, 4, 6, 7, 8, 9, 10-octahydropyrimido [1, 2-a ]]Azepine (11.0mL, 73.56mmol) followed by addition of the activated ester from part a and stirring of the mixture at ambient temperature for 16 h. The reaction was quenched with 50mL of water and most of the tetrahydrofuran was removed in vacuo. The remaining mixture was diluted with water (250mL) containing hydrochloric acid (26mL, 6M, 156.0mmol) and acidified to pH 2-3 the clear dark yellow solution was extracted with ethyl acetate (400mL) the organic phase was washed with 300mL brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give a thick yellow oil. Subjecting the crude reaction mixture to C ₁₈415g of reverse phase column chromatography, eluting with 50-100% water/acetonitrile to give (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (11.2g, 60%). ESI-MS M/z calculated 755.3232, Experimental value 756.3(M +1)⁺(ii) a Retention time: 2.53min (LC method B).

And step 3: 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl ] -N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] propylamino ] -2-pyridinyl ] sulfonyl ] pyridine-3-carboxamide (trifluoroacetate)

To a solution containing (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (16.7g, 22.08 mmol) in dichloromethane (80mL) and toluene (40mL) trifluoroacetic acid (10mL, 129.8mmol) was added and the mixture was stirred at ambient temperature for 22hThe oil was diluted with dichloromethane (80mL) and toluene (120mL) and the solvent was removed by rotary evaporation at 55 deg.C the process was repeated using dichloromethane and toluene to give 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl as a thick oil ]-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] radical]Propylamino group]-2-pyridyl]Sulfonyl radical]Pyridine-3-carboxamide (trifluoroacetate) (22.6g, 133%, product admixed with residual toluene and trifluoroacetic acid).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.73(s, 1H), 8.60 (s, 2H), 8.39(d, J ═ 2.9Hz, 1H), 8.11(d, J ═ 8.3Hz, 1H), 7.71(d, J ═ 8.4Hz, 1H), 7.63(dd, J ═ 8.5, 7.2Hz, 1H), 7.26-7.22(m, 1H), 6.75(dd, J ═ 8.5, 0.7Hz, 1H), 6.20 (d, J ═ 2.9Hz, 1H), 4.40(t, J ═ 6.8Hz, 2H), 3.36(dq, J ═ 12.0, 5.3Hz, 1H), 3.24(hept, J ═ 6.7, 2H), 2.80 (J ═ 8, 10.8, 1H), 3.5.3.24 (t, J ═ 6.7, 2H), 3.5.3.3.3.24 (hept, J ═ 6.7, 2H), 2.80(t, 8, 3.5.5, 3.5, 3.3.24 (H), 3.8, 3.6.6.6.5, 3, 3.8, 3.6.6.6.6.5 (H), 3.8, 3.3.3.3.3, 3.8, 1H), 3.5 (d, 3.3, 1H) 0.25-0.14(m, 2H), 0.11-0.00(m, 2H). ESI-MS M/z calculated 655.27075, Experimental 656.3(M +1)⁺(ii) a Retention time: 1.71min (LC method B).

And 4, step 4: (14S) -8- [3- (3, 3-Dicyclopropylpropoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 66)

To 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl]-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] radical]Propylamino group]-2-pyridyl]Sulfonyl radical]To a solution of pyridine-3-carboxamide (trifluoroacetate) (17.5g, 22.72 mmol) in NMP (300mL) was added potassium carbonate (15.3g, 110.7mmol) followed by cesium fluoride (3.8g, 25.02mmol). the mixture was purged with nitrogen for 5min. the mixture was heated at 150 ℃ for 20 h, the reaction mixture was cooled to room temperature, added to water (1200mL) (using a 5L flask cooled with an ice bath) and acidified by careful addition of hydrochloric acid (20mL, 6M, 120.0mmol) followed by addition of solid citric acid (45 g, 234.2 mmol.) the mixture was stirred in an ice bath for 1 h, the solid was collected by filtration using a medium pore glass frit (slow filtration) and the wet cake was dissolved in ethyl acetate (1, 000mL) and washed with 500 mL brine the aqueous phase was separated and the organic phase was dried over magnesium sulfate, filtered over celite and concentrated in vacuo to give a light yellow foam. The crude product was diluted with acetonitrile and divided into 3 equal volumes (15mL) and subjected to C ₁₈415g of reverse phase column chromatography, eluting with 50-100% acetonitrile/water to obtain (14S) -8- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 66) (8.91g, 63%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.48(s, 1H), 8.20(d, J ═ 3.2Hz, 1H), 7.81(d, J ═ 8.0Hz, 1H), 7.57(t, J ═ 7.8Hz, 1H), 7.05(d, J ═ 7.0Hz, 1H), 6.97(s, 2H), 6.71(d, J ═ 8.4Hz, 1H), 6.10(d, J ═ 3.2Hz, 1H), 4.37(t, J ═ 6.7Hz, 2H), 3.91(s, 1H), 3.15(s, 1H), 2.95(d, J ═ 13.3Hz, 1H), 2.71(s, 1H), 2.12(s, 1H), 1.95-1.71(m, 4H), 1.60(d, J ═ 13.3Hz, 1H), 1H, 2.71(s, 1H), 2.12(s, 1H), 1.95-1.71(m, 4H), 1.60(d, 3.3H), 3.3H, 1H), 4H, 7(d, 7H), 7H, 7 (m, 7H), 7H, 7 (m, 7H), 3.7H, 7H), 7H), 7H, 7, 0.04(d, J ═ 8.3Hz, 2H). ESI-MS M/z calculated 619.29407, Experimental 620.3(M +1)⁺(ii) a Retention time: 10.3min (LC method F).

Example 18: preparation of 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ] ]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 20-pentaazatetracyclo [17.2.2.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 1) (compound 72) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2λ⁶-thia-3, 9, 11, 18, 20-pentaazatetracyclo [17.2.2.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 2) (compound 73)

Step 1: 2, 2-dimethyl-4- [3- [ (5-sulfamoyl-2-pyridyl) amino ] propyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

To dimethyl sulfoxide (3.368mL) containing tert-butyl 4- (3-aminopropyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (400mg, 1.560mmol) and 6-chloropyridine-3-sulfonamide (300.5mg, 1.560mmol) was added potassium carbonate (219.9mg, 1.591mmol), and the mixture was stirred at 100 ℃ for 20h, then allowed to cool to room temperature, diluted with ethyl acetate and poured into a saturated aqueous solution of ammonium chloride, the layers were separated, then the organic layer was washed with a saturated aqueous salt solution, dried (sodium sulfate), filtered and concentrated to a yellow foam, the foam was purified by silica gel chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate to give 2, 2-dimethyl-4- [3- [ (5-sulfamoyl-2-pyridyl) amino group as a white solid. ]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (347mg, 54%). ESI-MS M/z calculated 412.21442, Experimental 413.2(M +1)⁺(ii) a Retention time: 0.52min (LC method A).

Step 2: 4- [3- [ [5- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

In a 20mL vial, 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]3-pyridinesThe acid (474.2mg, 1.262mmol) and carbonyldiimidazole (204.6mg, 1.262mmol) were combined in tetrahydrofuran (4.979mL) and stirred loose at 50 ℃ for 120 min. Followed by addition of a solution containing 2, 2-dimethyl-4- [3- [ (5-sulfamoyl-2-pyridyl) amino group]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (347mg, 0.8411mmol) in tetrahydrofuran (6.642mL) followed by the addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (251.6 μ L, 1.682 mmol) and the reaction was heated at 50 ℃ for 16 h the reaction was diluted with ethyl acetate and washed with a saturated aqueous solution of ammonium chloride followed by brine the organics were separated, dried over sodium sulfate, filtered and evaporated, then purified by silica gel chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate to give pure product and mixed fractions. The combined fractions were concentrated and subjected to reverse phase HPLC-MS using Luna C sold by Phenomenex ₁₈(2) The column (75 × 30mM, 5 μm particle size) (pn: 00C-4252-U0-AX) and re-purification was performed by 15.0min of a dual gradient run of 30-99% mobile phase B (mobile phase a ═ water (5mM hydrochloric acid), mobile phase B ═ acetonitrile, flow rate 50mL/min, injection volume 950 μ L, and column temperature 25 ℃). The pure fractions from the reverse phase preparative purification were combined and acetonitrile was removed by rotary evaporation the residue was dissolved in ethyl acetate and washed with a small amount of saturated aqueous sodium bicarbonate solution, followed by drying (sodium sulfate), filtration and concentration to a white solid, which was combined with the pure product from the silica gel column to give 4- [3- [ [5- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (539.2mg, 83%). ESI-MS M/z calculated 769.2636, Experimental 770.2(M +1)⁺(ii) a Retention time: 0.84min (LC method A).

And step 3: 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-3-yl) propylamino ] -3-pyridinyl ] sulfonyl ] -6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide

Will 4- [3- [ [5- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] methyl ester ]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (539.2 mg, 0.7000mmol) was dissolved in dichloromethane (2.353mL) and trifluoroacetic acid (2.474mL, 32.11mmol) was added to the mixture and the mixture was stirred at room temperature for 60 min. The mixture was concentrated to dryness under reduced pressure, dissolved in saturated aqueous sodium bicarbonate and ethyl acetate, and the layers were separated (the product was poorly soluble in ethyl acetate under these conditions, some methanol was added to help, the organic layer needed to be evaporated without the use of a solid desiccant.) the organic layer was concentrated by rotary evaporation, followed by vacuum drying to give 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-3-yl) propylamino as an off-white solid]-3-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (423.3mg, 90%). ESI-MS M/z calculated 669.2112, experimental 670.2(M +1)⁺(ii) a Retention time: 0.56min (LC method A).

And 4, step 4: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 20-pentaazatetracyclo [17.2.2.111, 14.05, 10 ]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 62)

To 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-3-yl) propylamino]-3-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]To a solution of pyridine-3-carboxamide (423.3mg, 0.6317mmol) in dimethyl sulfoxide (16.93mL) were added potassium carbonate (523.8mg, 3.790 mmol), cesium fluoride (115.1mg, 0.7577mmol) and a small amount

And (3) a molecular sieve. The resulting mixture was capped and heated to 165 ℃ for 16 h. Warmed to 175 ℃ and stirred for 3h, then cooled to room temperature and treated with ethyl acetateThe ester was diluted and washed with saturated aqueous ammonium chloride solution and brine. The organic phase was dried (sodium sulfate), filtered and concentrated to 500mg of brown amorphous solid, which was filtered and used the reverse phase HPLC-MS method using Luna C sold by Phenomenex₁₈(2) Column (75 × 30mM, 5 μm particle size) (pn: 00C-4252-U0-AX) and dual gradient run over 15.0min of 30-99% mobile phase B (mobile phase a ═ water (5mM hydrochloric acid), mobile phase B ═ acetonitrile, flow rate 50mL/min, injection volume 950 μ L, and column temperature 25 ℃) purification afforded 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] 8 as a white solid ]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 20-pentaazatetracyclo [17.2.2.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 62) (24.2mg, 6%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.13(s, 1H), 8.38(s, 1H), 8.17(d, J ═ 2.8Hz, 1H), 7.91-7.64 (M, 2H), 7.42(s, 1H), 6.63(d, J ═ 8.8Hz, 1H), 6.09(d, J ═ 2.7Hz, 1H), 4.30(t, J ═ 7.1Hz, 2H), 3.64(s, 1H), 2.88(s, 1H), 2.07(t, J ═ 7.1Hz, 3H), 2.03-1.92(M, 2H), 1.80-1.71(M, 1H), 1.54(s, 3H), 1.48(s, 3H), 1.38(q, J ═ 13.8, 11.4Hz, 4H), 0.92(M, 0.92), 0.92(M, 0.84), 0.83-3585M, M + M, 3H), calculated values (M, 3H), 1.8, 3H), M, 3H, M + 3585M, 3H, M⁺(ii) a Retention time: 2.03min (LC method B).

And 5: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 20-pentaazatetracyclo [17.2.2.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 1) (compound 72) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda ⁶-thia-3, 9, 11, 18, 20-pentaazatetracyclo [17.2.2.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 2) (compound 73)

By SFC chromatography, using ChiralPak AS-H (250X 10mM column, 5 μm particle size) and 18% methanol (20mM NH)₃Additive)/82% carbon dioxide mobile phase (10mL/min over 8.0min) (injected as a 70 μ L volume solution of 24mg/mL in 90% methanol/10% dimethylsulfoxide) to racemic 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ether]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 20-pentaazatetracyclo [17.2.2.111, 14.05, 10]The tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (17 mg, 0.02565mmol) was subjected to chiral separation to give 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] ketone as the first enantiomer to be eluted as a white solid]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 20-pentaazatetracyclo [17.2.2.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 1) (compound 72) (6.34mg, 78%); ESI-MS M/z calculated 633.2345, Experimental 634.4(M +1) ⁺(ii) a Retention time: 2.08min (LC method B), and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid as the second enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 20-pentaazatetracyclo [17.2.2.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 2) (compound 73) (5.54 mg, 68%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.13(s, 1H), 8.63(s, 1H), 8.43(s, 1H), 8.18(d, J ═ 2.8Hz, 1H), 7.89(d, J ═ 8.8Hz, 1H), 7.85(d, J ═ 8.4Hz, 1H), 7.54 (s, 1H), 6.90(dd, J ═ 8.3, 3.5Hz, 1H), 6.67(dd, J ═ 9.0, 3.1Hz, 1H), 6.11(d, J ═ 2.8Hz, 1H), 4.31(t, J ═ 7.0Hz, 2H), 3.66(s, 1H), 2.90(s, 1H), 2.08(d, J ═ 7.1Hz, 2H), 1.92(s, 3H), 1.77 (s, 1H), 3.6.48 (d, J ═ 7.1H, 1H), 1H, 19 (s, 3H), 3.6.6.6.6 (d, 1H), 3.6.19 (s, 1H), 3.6.19 (d, 19 (s, 1H), 3H), 3.6.6, 1H), 13 (d, 1H), 3.6, 1H), 3.6.6.6, 1H), 5(d, 1H), 3.6.6.6, 1H), 1H), 1H, experimental value 634.3(M +1)⁺(ii) a Retention time: 2.08min (LC method B).

Example 19: preparation of (14S) -12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ]Ethoxy } -1H-pyrazol-1-yl) -18-oxa-2. lambda⁶-thia-3, 9, 11-triazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 77)

From: (3S) -3- (3-hydroxypropyl) -5, 5-dimethyl-pyrrolidin-2-one

Racemic 3- (3-hydroxypropyl) -5, 5-dimethyl-pyrrolidin-2-one (100g, 566.5mmol) was separated by chiral SFC chromatography using ChiralPak AD-H (2 × 25cm column) and a 30% methanol/carbon dioxide mobile phase (60mL/min) (20 mg/mL solution in methanol injected at 1mL volume) to give (3S) -3- (3-hydroxypropyl) -5, 5-dimethyl-pyrrolidin-2-one as the first enantiomer to be eluted as an off-white solid (47 g, 48%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)7.63(s, 1H), 4.38(t, J ═ 5.1Hz, 1H), 3.39(t, J ═ 5.6Hz, 2H), 2.37(ddt, J ═ 13.9, 9.6, 4.4Hz, 1H), 2.02(dd, J ═ 12.3, 8.6 Hz, 1H), 1.78-1.64(m, 1H), 1.42(td, J ═ 12.8, 12.3, 8.4Hz, 3H), 1.16(d, J ═ 17.9 Hz, 7H). ESI-MS M/z calculated 171.12593, Experimental 172.0(M +1)⁺(ii) a Retention time: 0.61min (LC method B).

Step 2: 3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] propan-1-ol

A5L 3-neck round bottom flask was equipped with a mechanical stirrer, heating mantle, addition funnel, J-Kem temperature probe/controller, and nitrogen inlet/outletPellets (46.53g, 1.226 mmol). The vessel was then charged with tetrahydrofuran (500mL, 20 mL/g). Stirring was started and the pot temperature was recorded as 20 ℃. The mixture was stirred at room temperature for 0.5h to dissolve the pellets. The pot temperature of the resulting grey suspension was recorded as 24 ℃. A solution of (3S) -3- (3-hydroxypropyl) -5, 5-dimethyl-pyrrolidin-2-one (60 g, 350.4mmol) in tetrahydrofuran (600mL) was charged to the addition funnel and the clear pale yellow solution was added dropwise over 90 min. After the addition was complete, the pot temperature of the resulting light grey suspension was recorded as 24 ℃. The heating jacket was removed and the vessel was fitted with a cooling bath. The suspension was cooled to 0 ℃ with a crushed ice/water cooling bath and then quenched by very slow dropwise addition of water (46.53mL), followed by addition of 15 wt% sodium hydroxide solution (46.53mL) and then at the end with water (139.59 mL). The pot temperature of the resulting white suspension was recorded as 5 deg.c the cooling bath was removed and the vessel was again fitted with a heating mantle. The suspension was warmed to 60 ℃ and the conditions maintained for 30min the warm suspension was vacuum filtered through a frit buhner funnel with a 25mm celite layer, the filter cake was then displacement washed with 60 ℃ tetrahydrofuran (2 x 350mL) and then aspirated for 30min the clear filtrate was concentrated under reduced pressure to provide a clear pale yellow viscous oil (55g g, 0.349mol, 99% yield) as the desired product, i.e. 3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl) ]Propan-1-ol (55g, 100%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)3.36(t，J＝6.3Hz，3H)，2.95(dd，J＝10.6，7.6Hz， 1H)，2.40(dd，J＝10.6，7.7Hz，1H)，2.12-1.97(m，1H)，1.69(dd，J＝12.1，8.2Hz， 1H)，1.47-1.25(m，5H)，1.08(s，3H)，1.02(s，3H).

And step 3: (4S) -4- (3-hydroxypropyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

A1L 3-neck round bottom flask was equipped with a mechanical stirrer, cooling bath, addition funnel, J-Kem temperature probe, and nitrogen inlet/outlet. Charging a vessel with 3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl group under a nitrogen atmosphere]Propan-1-ol (25g, 159.0mmol) and dichloromethane (250mL) to provide a clear pale yellow solution stirring was started and the pot temperature recorded as 19 ℃. The addition funnel was charged with triethylamine (22.16g, 159.0mmol), which was then added drop wise over 5min without doping. No exotherm was observed. The addition funnel was then charged with di-tert-butyl dicarbonate (31.32g, 143.5mmol) dissolved in dichloromethane (150 mL). The clear pale yellow solution was then added dropwise over 30min, resulting in slight gas evolution. No exotherm was observed. The cooling bath was removed and the resulting clear pale yellow solution was allowed to warm to room temperature and stirring continued at room temperature for 3 h. The reaction mixture was transferred to a separatory funnel and partitioned with water (75 mL). The organics were removed and washed with a saturated solution of sodium chloride (75mL), dried over sodium sulfate (150g) and then filtered through a frit buchner funnel the filtrate was concentrated under reduced pressure to provide a clear pale yellow oil (45g) as the desired crude product. The material was purified by flash chromatography on silica gel column (liquid load with dichloromethane) eluting with a gradient of 100% dichloromethane to 10% methanol/dichloromethane over 60min, collecting 50mL fractions the desired product fractions were combined and concentrated under reduced pressure to provide (4S) -4- (3-hydroxypropyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (39g, 95%). ¹H NMR (400MHz, dimethylsulfoxide-d)₆)4.35(t, J ═ 5.2Hz, 1H), 3.54(dt, J ═ 12.2, 6.3Hz, 1H), 3.38(t, J ═ 5.8Hz, 2H), 2.76(q, J ═ 10.2Hz, 1H), 1.47 (s, 3H), 1.44-1.28(m, 18H), 1.24(s, 3H). ESI-MS M/z calculated 257.1991, Experimental 258.1(M +1)⁺(ii) a Retention time: 1.55min (LC method B).

And 4, step 4: (4S) -2, 2-dimethyl-4- (3-methanesulfonyloxypropyl) pyrrolidine-1-carboxylic acid tert-butyl ester

A 500mL 3-neck round bottom flask was equipped with a mechanical stirrer, a cooling bath, an addition funnel, a J-Kem temperature probe, and a nitrogen inlet/outlet the vessel was charged with (4S) -4- (3-hydroxypropyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (25g, 97.14mmol) and dichloromethane (250mL) under a nitrogen atmosphere to provide a clear colorless solution stirring was started and the pot temperature recorded as 19 ℃. The addition funnel was charged with triethylamine (17.60g, 126.3mmol), which was added drop wise over 5min without doping. The addition funnel was then charged with methanesulfonyl chloride (8.277mL, 106.9mmol) which was added drop wise over 15min without doping, yielding a pale yellow suspension and allowing an exotherm to 4 ℃. The reaction mixture was further diluted with dichloromethane (200mL) and then poured into a saturated solution of ammonium chloride (250 mL). The biphasic mixture was then transferred to a separatory funnel. The organics were removed, washed with a saturated solution of ammonium chloride (150mL), dried over sodium sulfate (150g) and then filtered through a frit buchner funnel. The filtrate was concentrated under reduced pressure to give tert-butyl (4S) -2, 2-dimethyl-4- (3-methanesulfonyloxypropyl) pyrrolidine-1-carboxylate as a clear amber oil (29g, 89%). ¹H NMR (400MHz, dimethylsulfoxide-d)₆)4.19(t, J ═ 6.4Hz, 2H), 3.16(s, 3H), 2.79(q, J ═ 10.2Hz, 1H), 2.11(s, 1H), 1.90(td, J ═ 13.5, 6.0Hz, 1H), 1.66(ddd, J ═ 15.8, 7.6, 4.0Hz, 2H), 1.51-1.22(m, 20H). ESI-MS M/z calculated 335.17664, Experimental 336.1(M +1)⁺(ii) a Retention time: 1.74min (LC method B).

And 5: (4S) -2, 2-dimethyl-4- [3- (3-sulfamoylphenoxy) propyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

In a 100mL flask was added 3-hydroxybenzenesulfonamide (750mg, 4.331mmol) and N, N-dimethylformamide (15mL). Potassium carbonate (1.8g, 13.02mmol) and(4S) -2, 2-dimethyl-4- (3-methanesulfonyloxypropyl) pyrrolidine-1-carboxylic acid tert-butyl ester (1.5g, 4.471 mmol.) the resulting mixture was stirred at room temperature for 48h, then heated to 50 ℃ for 5 h. The mixture was then poured into 1N citric acid and extracted with ethyl acetate (2 ×). The organic fractions were combined, dried (sodium sulfate), filtered and concentrated to a yellow oil which was purified via silica gel column chromatography (80 g column) using a gradient of 100% hexane to 65% ethyl acetate/hexane to give (4S) -2, 2-dimethyl-4- [3- (3-sulfamoylphenoxy) propyl ] as a light yellow foam ]Pyrrolidine-1-carboxylic acid tert-butyl ester (868mg, 49%).¹H NMR (400MHz, dimethylsulfoxide-d)₆) 7.47(t, J ═ 8.0Hz, 1H), 7.40-7.36(M, 1H), 7.34(d, J ═ 3.7Hz, 3H), 7.15(d, J ═ 8.3 Hz, 1H), 4.02(t, J ═ 6.1Hz, 2H), 3.58(dd, J ═ 17.4, 7.1Hz, 1H), 2.81(q, J ═ 10.3Hz, 1H), 2.15(s, 1H), 1.99-1.85(M, 1H), 1.74(dt, J ═ 13.3, 6.4Hz, 2H), 1.46(dd, J ═ 14.6, 9.4Hz, 3H), 1.38(t, J ═ 10.4, 12H), 1.25(s, 3H), 3.25H, M-25M + z + M/M + z calculated values (M, 1H) (+ 413M, 1H)⁺(ii) a Retention time: 1.86min (LC method E).

Step 6: (4S) -4- [3- [3- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] phenoxy ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (342mg, 0.9102mmol) and carbonyldiimidazole (148mg, 0.9127mmol) were combined in tetrahydrofuran (5.5mL) and stirred at 50 ℃ for 1h, then (4S) -2, 2-dimethyl-4- [3- (3-sulfamoylphenoxy) propyl]Pyrrolidine-1-carboxylic acid tert-butyl ester (250mg, 0.6060mmol) was added followed by 1, 8-diazabicyclo [5.4.0 ]Undec-7-ene (230 μ L, 1.538mmol) and the reaction was heated at 50 ℃ for 18h. Separating the organic substance, drying with sodium sulfateDrying, filtration and evaporation, and subsequent purification via silica gel chromatography (40 g column) using a gradient of 100% hexane to 75% ethyl acetate/hexane afforded (4S) -4- [3- [3- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] propyl ] as an off-white solid]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Phenoxy radical]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (368mg, 79%). ESI-MS M/z calculated 769.2524, Experimental 770.2 (M +1)⁺(ii) a Retention time: 2.12min (LC method G).

And 7: (14S) -12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -18-oxa-2. lambda⁶-thia-3, 9, 11-triazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 77)

Part A: (4S) -4- [3- [3- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] phenoxy ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (368mg, 0.4778mmol) was dissolved in dichloromethane (7.6mL), and hydrochloric acid (4M in dioxane) (4.0mL, 4M, 16.00mmol) was added to the mixture and stirred at room temperature for 30min the mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate, followed by addition of 2M aqueous sodium carbonate (5mL) to a pH of about 10. the organic layer was extracted with ethyl acetate (2 × 10mL), washed with brine, then dried over sodium sulfate, filtered, and evaporated to dryness under reduced pressure.

And part B: the material from part A was combined with potassium carbonate (345mg, 2.496mmol), cesium fluoride (115 mg, 0.7571mmol),

Molecular sieves and dimethylsulfoxide (7.6mL) were combined in a vial, purged with nitrogen, capped, heated at 150 ℃ and stirred for 20h, cooled to room temperature, the mixture filtered, then purified by reverse phase preparative HPLC utilizing C₁₈Column and method 30-99A1-B1 (acetonitrile-water)+5mM hydrochloric acid) to give (14S) -12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as an off-white solid]Ethoxy } -1H-pyrazol-1-yl) -18-oxa-2. lambda⁶-thia-3, 9, 11-triazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 77) (62.1mg, 20%).¹H NMR (400 MHz, dimethylsulfoxide-d)₆)12.40(s, 1H), 8.21(d, J ═ 2.8Hz, 1H), 7.85(d, J ═ 8.3Hz, 1H), 7.57(t, J ═ 6.5Hz, 2H), 7.50(s, 1H), 7.46-7.32(m, 1H), 6.94(d, J ═ 8.2Hz, 1H), 6.12(d, J ═ 2.7Hz, 1H), 4.34(dt, J ═ 14.1, 5.6, 3H), 4.21-4.04(m, 1H), 2.90-2.78 (m, ddh), 2.71 (m, ddh), 19.5, 9.2Hz, 1H), 2.26-2.12(m, 1H), 2.08(t, J ═ 7.1, 2.85 (H), 1.8, 1H), 1H, 6H, 1H, 6H, 1H, 2.6H, 1H, 2.6H, 2H, 8, 1H, 6H, 1H, 6H, and 1H, 2H) 0.88(t, J ═ 5.2Hz, 2H). ESI-MS M/z calculated 633.22327, Experimental 634.2(M +1) ⁺(ii) a Retention time: 2.3min (LC method E).

Example 20: preparation of (14S) -8- [3- (3, 3-dimethylbutyl) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 79)

Step 1: 3- (3, 3-dimethylbutyl) pyrrolidin-2-one

To a solution of 2-pyrrolidone (32.0g, 0.376mol) in anhydrous tetrahydrofuran (900mL) was added n-butyllithium (2.3M in hexane, 343mL, 0.790mol) at-78 ℃. The reaction mixture was stirred at the same temperature for 1 h. 1-chloro-3, 3-dimethylbutane (45.3g, 0.376mol) was reacted at-78 deg.CA solution in anhydrous tetrahydrofuran (100 mL) was added dropwise to the reaction mixture the reaction was stirred at-78 ℃ for 10min and then slowly warmed to room temperature. The reaction was quenched with 20% aqueous ammonium chloride (500 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2X 250 mL). The combined organic layers were washed with brine (300mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with hexanes (50mL) to give 3- (3, 3-dimethylbutyl) pyrrolidin-2-one as a white crystalline solid (9.091g, 14%). ¹H-NMR(250MHz， CDCl₃)5.70(s, br, 1H), 3.32(m, 2H), 2.29(m, 2H), 1.86(m, 1H), 1.79(m, 1H), 1.26(m, 3H), 0.90(s, 9H). ESI-MS m/z: calculated value 169.1, experimental value 169.9(M +1)⁺。

Step 2: (4S) -4- [3- [ [6- [ (2, 6-dichloropyridine-3-carbonyl) sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

A250 mL round bottom flask was charged with 2, 6-dichloropyridine-3-carboxylic acid (1.14g, 5.937mmol) and anhydrous tetrahydrofuran (20mL) under nitrogen. Carbonyldiimidazole (964mg, 5.945mmol) was added and the mixture was stirred at room temperature under nitrogen for 2h in a separate 100mL flask under nitrogen to prepare (4S) -2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino]Propyl radical]A solution of pyrrolidine-1-carboxylic acid tert-butyl ester (1.529g, 3.706 mmol) in anhydrous tetrahydrofuran (10mL) and then added to the activated ester solution by syringe 1, 8-diazabicyclo [5.4.0 ] was added by syringe]Undec-7-ene (1.2mL, 8.024mmol) and the reaction mixture was stirred at room temperature under nitrogen atmosphere for 16h, the solvent was removed under reduced pressure and the resulting thick oil was treated with ethyl acetate (50mL) and water (30mL), hydrochloric acid (4mL, 6M, 24.00mmol) was added and the two phases separated, the aqueous phase was washed with brine (30mL) and dried over sodium sulfate. After evaporation of the solvent, the residue was dissolved in dichloromethane and purified by flash chromatography on silica gel (80g column) using a gradient of ethyl acetate/hexane (0 to 100% over 30min) purification the solvent was evaporated to afford (4S) -4- [3- [ [6- [ (2, 6-dichloropyridine-3-carbonyl) sulfamoyl group as a white foamy solid]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.934g, 89%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.90 (width s, 1H), 8.06(dt, J ═ 8.0, 3.1Hz, 1H), 7.69(d, J ═ 8.0Hz, 1H), 7.61(dd, J ═ 8.5, 7.2Hz, 1H), 7.22 (width s, 1H), 7.16(d, J ═ 7.2Hz, 1H), 6.74(d, J ═ 8.5Hz, 1H), 3.61-3.41 (m, 1H), 3.31-3.13(m, 2H), 2.76(td, J ═ 10.5, 4.8Hz, 1H), 2.11-1.99(m, 1H), 1.83 (td, J ═ 14.1, 13.5, 5.9Hz, 1H), 1.60-1.44(m, 2.44), 1.26, 1H), 1.26(m, 1H), 3.21H). ESI-MS M/z calculated 585.15796, Experimental 586.1(M +1)⁺(ii) a Retention time: 2.02min (LC method B). The product was used in the next step without any further purification.

And step 3: 2, 6-diamino-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] propylamino ] -2-pyridinyl ] sulfonyl ] pyridine-3-carboxamide (dihydrochloride)

(4S) -4- [3- [ [6- [ (2, 6-dichloropyridine-3-carbonyl) sulfamoyl ] was stirred in a 100mL round bottom flask at room temperature in dichloromethane (10mL) and hydrochloric acid (3mL 4M in dioxane, 12.00mmol) ]-2-pyridyl]Amino group]Propyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (1.923g, 3.279 mmol.) white gummy precipitate formed rapidly adding dichloromethane (10mL) again and stirring the mixture at room temperature for a further 2.5 h. adding a further 2mL of hydrochloric acid and stirring the mixture for a further 2h. removing volatiles by evaporation and evaporating the residue in the presence of tetrahydrofuran/ethyl acetate/dichloromethane/methanol/hexane until a foamy solid is obtained]Propylamino group]-2-pyridyl]Sulfonyl radical]Pyridine-3-carboxamide (dihydrochloride) (1.933g, 105%) (approx. 90% pure by LCMS).¹H NMR (400MHz, two)Methyl sulfoxide-d₆)9.13 (width s, 1H), 8.98 (width s, 1H), 8.06(d, J ═ 8.0Hz, 1H), 7.72(d, J ═ 8.0Hz, 1H), 7.62(dd, J ═ 8.5, 7.2Hz, 1H), 7.17(d, J ═ 7.1Hz, 1H), 6.77(dd, J ═ 8.5, 0.8 Hz, 1H), 3.34(dq, J ═ 11.2, 5.6Hz, 1H), 3.24(q, J ═ 6.0Hz, 2H), 2.80(td, J ═ 11.8, 11.1, 6.0Hz, 1H), 2.42-2.29(M, 1H), 2.14(tt, J ═ 7.8, 6.9, 1H), 1.8 (dd, 1H), 7.83 (M, 7.8, 1H), 11.84 (dd, 7.8, 3.2H), 11.2.8, 7.8, 3.8, 3.2H, 7.3.3.3.2H, 11, 7.8, 3.3.3.3.3.3.2H, 11, 3.3.3.3, 3 ⁺(ii) a Retention time: 0.89min (LC method B).

And 4, step 4: (14S) -8-chloro-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound D)

Addition of 2, 6-dichloro-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] to a 20mL microwave vial under nitrogen]Propylamino group]-2-pyridyl]Sulfonyl radical]Pyridine-3-carboxamide (dihydrochloride) (859mg, 1.536 mmol), anhydrous NMP (13.5mL), potassium carbonate (1.4g, 10.13mmol) (325 mesh),

Molecular sieves and cesium fluoride (285mg, 1.876 mmol.) the vial was sealed under nitrogen and the mixture was stirred vigorously in an oil bath at 150 ℃ for 22h. the mixture was poured into cooling water (85mL) and acidified (light foaming) by the addition of hydrochloric acid (2.1 mL, 6M, 12.60 mmol). The resulting suspension was filtered through a ceramic funnel using filter paper, and the solid was air-dried approximately. The solid was dissolved in dichloromethane and dried over sodium sulfate. After concentration, the solution was diluted with dichloromethane and purified by silica gel chromatography using a gradient of ethyl acetate/hexane (0 to 100% over 30 min.) the product was eluted between 55-65% ethyl acetate/hexane the solvent was evaporated and further concentrated to afford (14S) -8-chloro-12, 12-dimethyl-2 λ ⁶-thia-3, 9, 11, 18,23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (320mg, 54%).¹H NMR (400MHz, chloroform-d) 9.19(s, 1H), 7.80(d, J ═ 7.9Hz, 1H), 7.56(t, J ═ 7.8 Hz, 1H), 7.44(d, J ═ 7.2Hz, 1H), 6.66(d, J ═ 7.9Hz, 1H), 6.59(d, J ═ 8.3Hz, 1H), 3.93(d, J ═ 11.0Hz, 1H), 3.25(dd, J ═ 10.1, 7.2Hz, 1H), 3.17(d, J ═ 13.6Hz, 1H), 2.96(t, J ═ 10.1Hz, 1H), 2.39(d, J ═ 9.7Hz, 1H), 1.96 (ESI, J ═ 12.1, 8, 1H), 1.7 (t, J ═ 10.1Hz, 1H), 2.39(d, J ═ 9.7Hz, 1H), 1.96 (ESI, J ═ 12, 8, J ═ 1H, 25 (J ═ 25H, 1H, 25H), 25H, 25(d, J ═ 1H), 25H, J ═ 1H, J ═ 4H, 15⁺(ii) a Retention time: 1.76min (LC method E).

And 5: (14S) -8- [3- (3, 3-dimethylbutyl) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 79)

A4 mL vial was charged with (14S) -8-chloro-12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (25mg, 0.05556 mmol), 3- (3, 3-dimethylbutyl) pyrrolidin-2-one (12mg, 0.07090mmol), Pd₂(dba)₃(8mg, 0.008736mmol), Xantphos (5mg, 0.008641mmol), cesium carbonate (99mg, 0.3038mmol), and anhydrous dioxane (400. mu.L). The mixture was aerated with nitrogen for 1-2min, capped and stirred at 120 ℃ for 21 h. The reaction was diluted with dimethyl sulfoxide (900 μ L), microfiltered, and subjected to reverse phase preparative HPLC (C) using a gradient of acetonitrile in water (1 to 99% over 15min) and hydrochloric acid as modifier (cl;)₁₈). The pure fractions were collected and the solvent was evaporated to give 4.3mg of an off-white solid the product was further purified by flash chromatography on silica gel (4g column) using a gradient of methanol/dichloromethane (0 to 5% over 30min). The pure fractions were collected and the solvent was evaporated to give (14S) -8- [3- (3, 3-dimethylbutyl) -2-oxopyrrolidin-1-yl as an off-white solid]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 79) (2mg, 6%) (diastereomeric mixtures). ¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.41(s, 1H), 7.68(d, J ═ 8.4Hz, 1H), 7.63-7.44 (M, 2H), 7.04(d, J ═ 7.1Hz, 1H), 6.97 (width s, 1H), 6.70(d, J ═ 8.5Hz, 1H), 4.16-3.64 (M, 3H), 3.10(br s, 1H), 2.94(d, J ═ 13.3Hz, 1H), 2.74-2.54(M, 2H), 2.29-2.17 (M, 1H), 2.10(br s, 1H), 1.87-1.43(M, 11H), 1.37-1.12(M, 6H), 0.88(d, J ═ 3.6Hz, 9H), ESI-MS/M, 3583, experimental calculated value (M + 85m + 84)⁺(ii) a Retention time: 2.25 min (LC method B).

Example 21: preparation of 12, 12-dimethyl-8- (4- {2- [1- (trifluoromethyl) cyclopropyl [)]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 82) and 12, 12-dimethyl-8- (4- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 83)

Step 1: 4-Hydroxypyrazole-1-carboxylic acid tert-butyl ester

Sodium hydroxide (16.32g, 408.0mmol) was added to tert-butyl 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole-1-carboxylate (60g, 204.0mmol) in tetrahydrofuran (450mL) at low temperature (0 deg.C), followed by slow addition of hydrogen peroxide (46.26g, 41.68mL, 30% w/v, 408.0 mmol.) the reaction mixture was stirred at 0 deg.C for 10min, then at room temperature for 45min, the reaction was cooled to 0 deg.C and diluted with dichloromethane (800 mL). 3M hydrochloric acid was added until pH 2, and the organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure the residue was triturated in a small amount of dichloromethane and the solid was filtered under vacuum, washed well again with dichloromethane and dried under reduced pressure to give 4-hydroxypyrazole-1-carboxylic acid tert-butyl ester as a white solid (19.904g, 53%).¹H NMR (300MHz, dimethylsulfoxide-d)₆)1.52(s, 9H), 7.45(d, J ═ 0.9Hz, 1H), 7.51(d, J ═ 0.9Hz, 1H), 9.28(s, 1H). ESI-MS M/z calculated 184.0848, Experimental 129.1(M-C4H8+1)⁺(ii) a Retention time: 1.73min (LC method H).

Step 2: 4- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazole-1-carboxylic acid tert-butyl ester

2- [1- (trifluoromethyl) cyclopropyl at 0 deg.C]Ethanol (28.2g, 183.0mmol) was added to a solution of tert-butyl 4-hydroxypyrazole-1-carboxylate (23.7g, 128.7mmol) and triphenylphosphine (50.6g, 192.9mmol) in tetrahydrofuran (250 mL.) diisopropyl azodicarboxylate (39.03g, 38.00mL, 193.0mmol) was added slowly at 0 ℃ and the reaction mixture was stirred at 0 ℃ for 10min. the reaction was then heated at 70 ℃ overnight. the reaction was cooled to room temperature and the reaction mixture was diluted with dichloromethane (300mL) and quenched by the addition of 5% aqueous citric acid (150 mL.) the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure (155g yellow oil). the residue triturated with heptane and a small amount of ethyl acetate (less than 10%), the solid was filtered and washed with heptane. The filtrate (55g of yellow oil) was concentrated under reduced pressure the residue was purified by silica gel chromatography using a gradient of 0% to 20% ethyl acetate in heptane to give 4- [2- [1- (trifluoromethyl) cyclopropyl ] as a white solid ]Ethoxy radical]Pyrazole-1-carboxylic acid tert-butyl ester (27.31 g)，66％).¹H NMR (300MHz, dimethylsulfoxide-d)₆)0.80-0.97(M, 4H), 1.54(s, 9H), 2.00(t, J ═ 6.9Hz, 2H), 3.99(t, J ═ 6.8Hz, 2H), 7.61-7.70(M, 1H), 7.90(s, 1H), 19F NMR (282MHz, dimethyl sulfoxide-d 6) -68.6(s, 3F), ESI-MS M/z calculated 320.1348, experimental 265.1(M-C4H8+1)⁺(ii) a Retention time: 2.18min (LC method I).

And step 3: 4- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] -1H-pyrazole (hydrochloride)

Hydrogen chloride (80mL, 4M, 320.0mmol) was added to 4- [2- [1- (trifluoromethyl) cyclopropyl ] amine]Ethoxy radical]Pyrazole-1-carboxylic acid tert-butyl ester (10.63g, 33.19mmol) in dichloromethane (50mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give 4- [2- [1- (trifluoromethyl) cyclopropyl ] as an off-white solid]Ethoxy radical]-1H-pyrazole (hydrochloride) (8.71g, 100%).¹H NMR (300MHz, dimethylsulfoxide-d)₆)0.77-0.96(M, 4H), 1.98(t, J ═ 6.9Hz, 2H), 3.91(t, J ═ 6.9Hz, 2H), 7.41(s, 2H), ESI-MS M/z calculated 220.0823, experimental 221.2(M +1)⁺(ii) a Retention time: 2.43 min (LC method H).

And 4, step 4: 2-chloro-6- [4- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxylic acid tert-butyl ester

4- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]-1H-pyrazole (hydrochloride) (10g, 38.963mmol) was added to N, N-dimethylformamide (80mL) the reaction was cooled to 0 ℃ and sodium hydride (1.87g, 60% w/w, 46.754mmol) was added portionwise and stirred for 10min, a solution of tert-butyl 2, 6-dichloropyridine-3-carboxylate (9.67g, 38.975mmol) in N, N-dimethylformamide (20mL) was added and the reaction was heated at 75 ℃ and stirred overnightCool to room temperature, quench the reaction with brine (100mL) and extract with ethyl acetate (3 × 50 mL.) the organic layers are combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0% to 10% ethyl acetate/heptane to give 2-chloro-6- [4- [2- [1- (trifluoromethyl) cyclopropyl ] propyl as a white solid]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (7.68g, 46%).¹H NMR(300MHz，CDCl₃)0.73(s, 2H), 0.98-1.10(M, 2H), 1.62(s, 9H), 2.03-2.13(M, 2H), 4.09(t, J ═ 7.0Hz, 2H), 7.51(s, 1H), 7.84(d, J ═ 8.5Hz, 1H), 8.12(s, 1H), 8.21(d, J ═ 8.5Hz, 1H), 19F NMR (282MHz, CDCl3) -69.9(br.s., 3F), ESI-MS M/z calculated 431.1224, experimental 432.1(M +1) + +; retention time: 2.56min (LC method I).

And 5: 2-chloro-6- [4- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxylic acid

Trifluoroacetic acid (46.620g, 31.5mL, 408.86mmol) was added to 2-chloro-6- [4- [2- [1- (trifluoromethyl) cyclopropyl ] amine]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (17.59g, 40.733mmol) in dichloromethane (150mL) and the reaction mixture was stirred at room temperature for 4h. The residue was diluted with ethyl acetate (175mL) and the organic layer was washed with brine (2 × 100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give crude 2-chloro-6- [4- [2- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (14.82g, 77%).¹H NMR (300MHz, dimethylsulfoxide-d)₆)0.81-0.97(M, 4H), 2.04(t, J ═ 6.9Hz, 2H), 4.04-4.13(M, 2H), 7.77(s, 1H), 7.86(d, J ═ 8.5Hz, 1H), 8.25(s, 1H), 8.37(d, J ═ 8.5Hz, 1H), ESI-MS M/z calculated 375.0598, experimental 376.1(M +1)⁺(ii) a Retention time: 3.14min (LC method H).

Step 6: 4- [4- [ [6- [ [ 2-chloro-6- [4- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] butyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

Adding 2-chloro-6- [4- [2- [1- (trifluoromethyl) cyclopropyl ] to a round bottom flask]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (97mg, 0.2582mmol), carbonyldiimidazole (45mg, 0.2775mmol) and tetrahydrofuran (3.0 mL). The reaction was heated at 40 ℃ for 90 min. Dropwise addition of 2, 2-dimethyl-4- [4- [ (6-sulfamoyl-2-pyridyl) amino group]Butyl radical]A solution of pyrrolidine-1-carboxylic acid tert-butyl ester (95mg, 0.2227mmol) in tetrahydrofuran (2mL) was added followed by 2, 3, 4, 6, 7, 8, 9, 10-octahydropyrimido [1, 2-a ]]Azepine (120. mu.L, 0.8024 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched with 1N citric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated the crude reaction mixture was purified by HPLC (20% -99% acetonitrile: water + 0.1% hydrochloric acid modifier) to give 4- [4- [ [6- [ [ 2-chloro-6- [4- [2- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Butyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (82.7mg, 49%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.81 (s, 1H), 8.24(s, 1H), 8.11(d, J ═ 8.4Hz, 1H), 7.87(d, J ═ 8.4Hz, 1H), 7.77(d, J ═ 0.9 Hz, 1H), 7.61(dd, J ═ 8.5, 7.2Hz, 1H), 7.20(d, J ═ 4.9Hz, 1H), 7.16(d, J ═ 7.2Hz, 1H), 6.73(d, J ═ 8.5Hz, 1H), 4.09(t, J ═ 6.9Hz, 2H), 3.54-3.41(m, 1H), 3.22(q, J ═ 6.5Hz, 2H), 2.74-2.63(m, 1H), 2.05(t, 6.6, J ═ 1H), 2.7.7.8, 1H), 7.31 (d, 1H), 1H, 7.5H, 1H, 7.9H, 1H, and 1H. ESI-MS M/z calculated 783.27924, Experimental 784.3(M +1) ⁺(ii) a Retention time: 2.28min (LC method B).

And 7: 2-chloro-N- [ [6- [4- (5, 5-dimethylpyrrolidin-3-yl) butylamino ] -2-pyridinyl ] sulfonyl ] -6- [4- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide

To a solution containing 4- [4- [ [6- [ [ 2-chloro-6- [4- [2- [1- (trifluoromethyl) cyclopropyl ] group]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Butyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (118 mg, 0.1505mmol) in a round bottom flask was added dichloromethane (5mL) and trifluoroacetic acid (650 μ L, 8.437 mmol). The reaction was stirred at room temperature for 1h, evaporated to dryness, saturated solution of sodium bicarbonate was added, followed by ethyl acetate, the reaction was extracted 3 times with ethyl acetate, dried over sodium sulfate, filtered and evaporated to give 2-chloro-N- [ [6- [4- (5, 5-dimethylpyrrolidin-3-yl) butylamino]-2-pyridyl]Sulfonyl radical]-6- [4- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (102mg, 99%) was used without further purification. ESI-MS M/z calculated 683.2268, Experimental 684.4(M +1)⁺(ii) a Retention time: 1.51min (LC method B).

And 8: 12, 12-dimethyl-8- (4- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester ]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (compound 70)

To a microwave vial was added potassium carbonate (92mg, 0.6657mmol), cesium fluoride (45mg, 0.2962 mmol), five

Molecular sieves and 2-chloro-N- [ [6- [4- (5, 5-dimethylpyrrolidin-3-yl) butylamino]-2-pyridyl]Sulfonyl radical]-6- [4- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Solution of pyridine-3-carboxamide (90 mg, 0.1315mmol) in dimethylsulfoxide (0.8 mL.) A solution of pyridine-3-carboxamide in dimethylsulfoxide (0.8mL) was preparedThe reaction was sealed and placed in a preheated 150 ℃ oil bath overnight the reaction was cooled to room temperature, filtered and purified by HPLC (10% -99% acetonitrile: water + 0.1% hydrochloric acid modifier) to give 12, 12-dimethyl-8- (4- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (compound 70) (20.8mg, 24%). ESI-MS M/z calculated 647.2502, Experimental 648.4(M +1)⁺(ii) a Retention time: 2.1min (LC method B).

And step 9: 12, 12-dimethyl-8- (4- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 82) and 12, 12-dimethyl-8- (4- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 83)

ChiralPak AS-H (250X 21.2mm column, 5 μm particle size) and 20% -25% methanol (NH) were used₃Modifier)/carbon dioxide mobile phase (50mL/min) to racemic 12, 12-dimethyl-8- (4- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.111, 14.05, 10]Eicosapentaenoic-1- (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (17mg, 0.02625mmol) was subjected to chiral SFC chromatography to give 12, 12-dimethyl-8- (4- {2- [1- (trifluoromethyl) cyclopropyl ] ketone as the first enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -2 lambda ⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.111, 14.05, 10]Pentacosal-1 (23), 5, 7, 9, 20(24), 21-hexaene-2, 2, 4-trione (enantiomer 1) (compound 82) (7.7mg, 90%); ESI-MS M/z calculated 647.2502, Experimental 648.2(M +1)⁺(ii) a Retention time: 3.18min (LC method D) and 12, 12-dimethyl-8- (4- {2- [1- (trifluoromethyl) cyclopropyl ] as the second enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 83) (7.6mg, 89%);¹h NMR (400MHz, dimethylsulfoxide-d)₆)12.49(s, 1H), 7.96(d, J ═ 1.0Hz, 1H), 7.82(d, J ═ 8.2Hz, 1H), 7.62(d, J ═ 26.0Hz, 2H), 7.14(s, 1H), 6.98(s, 1H), 6.69(d, J ═ 44.0 Hz, 2H), 4.06(t, J ═ 7.1Hz, 2H), 2.86(s, 1H), 2.04(t, J ═ 7.0Hz, 3H), 1.88-1.78(M, 1H), 1.65-1.47(M, 7H), 1.21(d, J ═ 14.6Hz, 3H), 1.01-0.82(M, 4H), calculated ESI-MS 647.2502, experimental value 648.2(M + 1H)⁺(ii) a Retention time: 3.18min (LC method D).

Example 22: preparation of (18R) -20, 20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] -amide]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]

Docosac

2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (compound 84) and (18S) -20, 20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]

Docosac

2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (Compound 85)

Step 1: 2, 2-dimethyl-4- [3- (3-sulfamoylpyrazol-1-yl) propyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

Part A: to dry dichloromethane (100mL) containing 4- (3-hydroxypropyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (10g, 38.85mmol) in a 250mL round bottom flask was added triethylamine (8.3mL, 59.55 mmol), the reaction was cooled to 0 ℃ over 10min and methanesulfonyl chloride (3.7mL, 47.80mmol) was added dropwise (exothermic, forming a white slurry), and the reaction was stirred for 1h while warming to room temperature. The organic layer was dried over sodium sulfate, filtered and evaporated to afford the mesylate as a yellowish oil.

And part B: the crude mesylate from part a was dissolved in N, N-dimethylformamide (50mL) and 1H-pyrazole-3-sulfonamide (5.8g, 39.41mmol) was added, followed by potassium carbonate (16.3g, 117.9mmol) and the reaction mixture was stirred at 70 ℃ for 20H the reaction mixture was cooled to room temperature and poured into crushed ice and extracted with ethyl acetate (3 × 100mL), the organic layers combined, washed with water (2 ═ × 100mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The brown residue was purified by silica gel chromatography (330 g column) using a gradient of 100% hexane to 100% ethyl acetate to give 2, 2-dimethyl-4- [3- (3-sulfamoylpyrazol-1-yl) propyl ] as a white solid]Pyrrolidine-1-carboxylic acid tert-butyl ester (7.6g, 51%). ESI-MS M/z calculated 386.19876, Experimental 387.25(M +1)⁺(ii) a Retention time: 0.61min (LC method A).

Step 2: 4- [3- [3- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] pyrazol-1-yl ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (458mg, 1.219mmol) and bis (imidazol-1-yl) methanone (208mg, 1.283mmol) were combined in tetrahydrofuran (5mL) and stirred at 50 ℃ for 120 min. Subsequently, 2-dimethyl-4- [3- (3-sulfamoylpyrazol-1-yl) propyl ] is added ]Pyrrolidine-1-carboxylic acid tert-butyl ester(388mg, 1.004mmol) followed by the addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (300 μ L, 2.006mmol) and the reaction stirred at room temperature for 20 h. The organics were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexane to 90% ethyl acetate/hexane to give 4- [3- [3- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Pyrazol-1-yl]Propyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (247mg, 33%).¹H NMR (400MHz, chloroform-d) 9.82(s, 1H), 8.30(d, J ═ 2.9Hz, 1H), 8.22(d, J ═ 8.5Hz, 1H), 7.73(d, J ═ 8.5Hz, 1H), 7.47(d, J ═ 2.4Hz, 1H), 7.04(d, J ═ 2.3Hz, 1H), 5.96(d, J ═ 2.9Hz, 1H), 4.39(t, J ═ 7.2Hz, 2H), 4.19(t, J ═ 7.1Hz, 2H), 3.75-3.51(m, 1H), 2.83(t, J ═ 10.3Hz, 1H), 2.08(t, J ═ 7.2Hz, 2H), 1.87 (J ═ 83, 19, 1H), 3.857.31H), 2.83 (m, 1H), 3.3.857.3H, 3H), 3.3.3H, 1H, 19 (m, 1H), 3.3.3H, 19(t, 19, 3H), 3H, 19(t, 3H, 19, 3H), 3H), 15.3H, 3H), 2.3H, 3H), 2.3H, 3H, 15, 3H, experimental value 744.3(M +1) ⁺(ii) a Retention time: 0.86min (LC method A).

And step 3: 20, 20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]

Docosac

2, 4, 6, 11(22), 12-pentaen-8, 10, 10-triones

Part A: a solution of tert-butyl 4- [3- [3- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] pyrazol-1-yl ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylate (247 mg, 0.3319mmol) in dichloromethane (1mL) and (260. mu.L, 3.398mmol) was stirred at room temperature for 4 h. The residue was dissolved in ethyl acetate, washed with 2mL of a saturated solution of sodium bicarbonate, and the solvent was removed and dried under high vacuum.

And part B: the residue from part A was dissolved in dimethyl sulfoxide (6mL) and added

Molecular sieves and stir the reaction mixture for 10 min. Cesium fluoride (153mg, 1.007mmol) and potassium carbonate (142mg, 1.027mmol) were then added and the reaction mixture was heated at 130 ℃ overnight. The reaction mixture was filtered through Whatman filter disc (puradisc 25TF) and the filtrate was purified by reverse phase HPLC-MS method using a double gradient run of 50-90% mobile phase B over 15.0min (mobile phase a ═ water (0.05% hydrochloric acid), mobile phase B ═ acetonitrile) to give 20, 20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid ]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosate 2(7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (80mg, 40%). ESI-MS M/z calculated 607.2189, Experimental 608.1(M +1)⁺(ii) a Retention time: 2.07min (LC method B).

And 4, step 4: (18R) -20, 20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]

Docosac

2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (Compound 85)

The elimination was carried out by SFC chromatography using Chiral Pak AS-H (250X 10mm column, 5 μm particle size) and a 27% acetonitrile/methanol, 73% carbon dioxide mobile phase (10mL/min over 8.0min) (infusion volume 70 μ L about 24 mg/mL in acetonitrile/methanol (90: 10)) usingSpiro 20, 20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda ⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]The docosate 2(7), 3, 5, 11(22), 12-pentaen-8, 10, 10-trione (80mg) was subjected to chiral separation to give (18R) -20, 20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] ketone as the first enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -10 lambda 6-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac 2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (compound 84) (27mg, 27%);¹h NMR (400MHz, chloroform-d) 8.82(s, 1H), 8.16(d, J ═ 2.8Hz, 1H), 7.66(d, J ═ 8.2Hz, 1H), 7.46(d, J ═ 2.4Hz, 1H), 7.06(d, J ═ 2.3Hz, 1H), 6.96(d, J ═ 8.2Hz, 2H), 5.86(d, J ═ 2.8Hz, 1H), 4.39(d, J ═ 7.1Hz, 2H), 4.31(dt, J ═ 13.3, 3.3Hz, 1H), 3.91(td, J ═ 12.8, 2.7Hz, 2H), 2.81-2.66(m, 2H), 2.19-2.07(m, 3H), 1.97(t, J ═ 12.8, 2.7Hz, 2H), 2.81-2.66(m, 2H), 2.19-19 (m, 3H), 1.97(t, J ═ 1.7, 1, 1.7H), 1, 1.7H, 7H, 5 (m, 1.7H), 5 (m, 1H, 1, 7H), 7H), 5 (m, 1, 1.7H), 5 (m, 1.7H), 5H), experimental value 608.1(M +1) +; retention time: 2.07min (LC method B) and (18S) -20, 20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as the second enantiomer to be eluted ]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac 2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (compound 85) (31.5mg, 31%);¹h NMR (400MHz, chloroform-d) 8.44(s, 1H), 8.17(d, J ═ 2.7Hz, 1H), 7.68(d, J ═ 8.2Hz, 1H), 7.48(d, J ═ 2.3Hz, 1H), 7.07(d, J ═ 2.3Hz, 1H), 7.00 (d, J ═ 8.3Hz, 1H), 5.86(d, J ═ 2.7Hz, 1H), 4.39(d, J ═ 7.2Hz, 2H), 4.33(d, J ═ 3.5 Hz, 1H), 3.93(t, J ═ 12.3Hz, 1H), 2.74(s, 1H), 2.22-2.12(m, 2H), 2.09(t, J ═ 7.2, 1H), 2.99 (t, J ═ 12.3Hz, 1H), 2.9.9H, 9 (H, 9, 9.9H, 1H), 9.9, 9 (H, 1H), 9, 1H, 9, 1H), 9, 1H, 9, 1H), ESI-MS M/z calculated 607.2189, Experimental 608.1(M +1)⁺(ii) a Retention time: 2.07 min (LC method B).

Example 23: preparation of 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda⁶-thia-3, 9, 11-triazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (22), 5, 7, 9, 20, 23-hexaen-2, 2, 4-trione (enantiomer 1) (compound 95) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda⁶-thia-3, 9, 11-triazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (22), 5, 7, 9, 20, 23-hexaen-2, 2, 4-trione (enantiomer 2) (compound 96)

Step 1: 2, 2-dimethyl-4- [4- (4-sulfamoylphenoxy) butyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

In a 50mL flask was added 4-hydroxybenzenesulfonamide (319mg, 1.842mmol) and N, N-dimethylformamide (12.88mL). Tert-butyl 2, 2-dimethyl-4- (4-methylsulfonyloxybutyl) pyrrolidine-1-carboxylate (643.8mg, 1.842mmol) and potassium carbonate (891mg, 6.447mmol) were added to the mixture at room temperature and stirred at 50 ℃ overnight. Cooled to room temperature and poured into water (100mL) and extracted with ethyl acetate (2 × 100mL), the organic layers were combined, washed with water (2 × 100mL), dried (sodium sulfate), filtered and concentrated to a brown residue which was purified by silica gel chromatography using a gradient of 100% hexane to 100% ethyl acetate to give 2, 2-dimethyl-4- [4- (4-sulfamoylphenoxy) butyl ] phenoxy as a light orange oil]Pyrrolidine-1-carboxylic acid tert-butyl ester (416.1mg, 53%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)7.46(t，J＝8.0Hz，1H)， 7.39-7.33(m，2H)，7.31(s，2H)，7.13(d，J＝7.8Hz，1H)，4.02(t，J＝6.0Hz，2H)， 3.85-3.67(m，1H)，1.88(dd, J ═ 11.8, 6.6Hz, 2H), 1.79-1.61(m, 4H), 1.51(dd, J ═ 37.7, 5.8Hz, 2H), 1.38(s, 12H), 1.24(s, 3H). ESI-MS M/z calculated 426.21884, Experimental 427.3(M +1) ⁺(ii) a Retention time: 0.75min (LC method A).

Step 2: 4- [4- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] phenoxy ] butyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

In a 20mL vial, 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (549.7mg, 1.463mmol) and carbonyldiimidazole (237.2mg, 1.463mmol) were combined in tetrahydrofuran (5.971mL) and stirred loose at 50 ℃ for 120min, then, 2-dimethyl-4- [4- (4-sulfamoylphenoxy) butyl-containing solution was added]Pyrrolidine-1-carboxylic acid tert-butyl ester (416.1mg, 0.9755mmol) in tetrahydrofuran (7.964mL) followed by the addition of 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene (297.0mg, 291.7 μ L, 1.951mmol) and heating the reaction at 50 ℃ for 16 h. the reaction was diluted with ethyl acetate and washed with a saturated aqueous solution of ammonium chloride followed by brine the organics were separated, dried over sodium sulfate, filtered and evaporated, then purified by silica gel chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate resulting in extremely poor separation the product containing fractions were combined and concentrated, then repurified by silica gel chromatography using a gentle gradient of 100% dichloromethane to 20% methanol/dichloromethane to give 4- [4- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] as a pale yellow solid ]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Phenoxy radical]Butyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (596mg, 78%). ESI-MS M/z calculated 783.268, Experimental 784.2(M +1)⁺(ii) a Retention time: 2.54min (LC method B).

And step 3: 2-chloro-N- [4- [4- (5, 5-dimethylpyrrolidin-3-yl) butoxy ] phenyl ] sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide

4- [4- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] group]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Phenoxy radical]Butyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (596mg, 0.7599mmol) was dissolved in dichloromethane (2.600mL) and trifluoroacetic acid (3.975g, 2.686mL, 34.86mmol) was added to the mixture and stirred at room temperature for 60min. The organic layer was concentrated by rotary evaporation, followed by high vacuum pump to give 2-chloro-N- [4- [4- (5, 5-dimethylpyrrolidin-3-yl) butoxy as an off-white solid]Phenyl radical]Sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (403.3mg, 78%). ESI-MS M/z calculated 683.2156, Experimental 684.2 (M +1)⁺(ii) a Retention time: 0.66min (LC method A).

And 4, step 4: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda⁶-thia-3, 9, 11-triazatetracyclo [18.2.2.111, 14.05, 10]Pentacosan-1 (22), 5, 7, 9, 20, 23-hexaen-2, 2, 4-trione (compound 89)

To 2-chloro-N- [4- [4- (5, 5-dimethylpyrrolidin-3-yl) butoxy]Phenyl radical]Sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]To a solution of pyridine-3-carboxamide (403.3mg, 0.5895mmol) in dimethyl sulfoxide (16.13mL) were added potassium carbonate (488.7mg, 3.536mmol), cesium fluoride (107.5mg, 0.7077mmol) and a small amount

Mixing the obtained mixtureThe mixture was capped and heated to 165 ℃ for 18h, then the mixture was cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution and brine the organic phase was dried (sodium sulfate), filtered and concentrated to a brown amorphous solid which was purified by silica gel chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate to give 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl acetate ]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda⁶-thia-3, 9, 11-triazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (22), 5, 7, 9, 20, 23-hexaen-2, 2, 4-trione (compound 89) (80mg, 21%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.22(s, 1H), 8.19(d, J ═ 2.8 Hz, 1H), 8.08(dd, J ═ 8.6, 2.5Hz, 1H), 7.88(d, J ═ 8.3Hz, 1H), 7.77(dd, J ═ 8.7, 2.5Hz, 1H), 7.34(ddd, J ═ 16.6, 8.7, 2.5Hz, 2H), 6.92(d, J ═ 8.3Hz, 1H), 6.11(d, J ═ 2.7Hz, 1H), 4.40(t, J ═ 4.8Hz, 2H), 4.31(t, J ═ 7.0Hz, 2H), 2.40(s, 1H), 2.07(t, J ═ 7.1, 2H), 1H, 5H, 1H, 6.5H, 5H, 6.6.6.6.6.6 (d, 1H, 5H, 1H, 6.6, 1H, 6H, and 1H, 4.0Hz, 2H), 0.88(s, 2H), 0.67(s, 1H), ESI-MS M/z Calcd 647.23895, Experimental 648.2(M +1)⁺(ii) a Retention time: 2.37min (LC method B).

And 5: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda⁶-thia-3, 9, 11-triazatetracyclo [18.2.2.111, 14.05, 10 ]Pentacosac-1 (22), 5, 7, 9, 20, 23-hexaen-2, 2, 4-trione (enantiomer 1) (compound 95) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda⁶-thia-3, 9, 11-triazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (22), 5, 7, 9, 20, 23-hexaen-2, 2, 4-trione (enantiomer 2) (compound 96)

Racemic 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] c-8 was chromatographed by SFC using ChiralCel OD-H (250 × 10mm column, 5 μm particle size) and 35% acetonitrile/methanol (90: 10)/65% carbon dioxide mobile phase (10mL/min over 8.0min) (infusion volume ═ 70 μ L of 24mg/mL solution in acetonitrile methanol (90: 10))]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda⁶-thia-3, 9, 11-triazatetracyclo [18.2.2.111, 14.05, 10]The pentacosac-1 (22), 5, 7, 9, 20, 23-hexaen-2, 2, 4-trione (compound 89) (72.1 mg, 0.1101mmol) was subjected to chiral separation to give 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] ketone as the first enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda⁶-thia-3, 9, 11-triazatetracyclo [18.2.2.111, 14.05, 10 ]Pentacosac-1 (22), 5, 7, 9, 20, 23-hexaen-2, 2, 4-trione (enantiomer 1) (compound 95) (21.9mg, 61%);¹h NMR (400MHz, dimethylsulfoxide-d)₆) 12.23(s, 1H), 8.19(d, J ═ 2.8Hz, 1H), 8.08(dd, J ═ 8.6, 2.4Hz, 1H), 7.88(d, J ═ 8.3Hz, 1H), 7.76(dd, J ═ 8.7, 2.4Hz, 1H), 7.34(ddd, J ═ 16.3, 8.7, 2.5Hz, 2H), 6.92(d, J ═ 8.3Hz, 1H), 6.11(d, J ═ 2.7Hz, 1H), 4.40(t, J ═ 4.9Hz, 2H), 4.31(t, J ═ 7.0Hz, 2H), 3.17(d, J ═ 5.2, 1H), 2.40(d, J ═ 10.2H), 1.31 (t, J ═ 7.0Hz, 2H), 3.17(d, J ═ 5.2, 1H), 1H, 2.40(d, J ═ 10.2, 1.2, 1H), 1H, 1.81, 1H, 13 (d, 1.7H), 1H), 1.7H, 1H, 13 (d, 13, 7H), 3.7H), 0.98-0.94(M, 2H), 0.88(tt, J ═ 5.6, 2.4Hz, 2H), 0.66(d, J ═ 13.0Hz, 1H), ESI-MS M/z calculated 647.23895, experimental 648.2(M +1)⁺(ii) a Retention time: 2.34min (LC method B) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as the second enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda⁶-thia-3, 9, 11-triazatetracyclo [18.2.2.111, 14.05, 10 ]Pentacosac-1 (22), 5, 7, 9, 20, 23-hexaen-2, 2, 4-trione (enantiomer 2) (compound 96) (18.75mg, 52%); ESI-MS M/z calculated 647.23895, Experimental 648.2(M +1)⁺(ii) a Retention time: 2.33min (LC method B).

Example 24: preparation of (14S) -8- [3- (3, 3-dimethylbutyl) -4, 4-dimethyl-2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (hydrochloride) (Compound 98)

Step 1: 1-benzyl-4, 4-dimethyl-pyrrolidin-2-one

To a 100mL round bottom flask charged with 4, 4-dimethylpyrrolidin-2-one (524mg, 4.631mmol) was added tetrahydrofuran (25mL), followed by 2-methylpropan-2-ol salt (sodium salt) (590mg, 6.139mmol), and the mixture was stirred at room temperature for 30 min. Bromomethylbenzene (1000 μ L, 8.408mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction was quenched with water (ca 15mL) and the crude mixture was extracted with ethyl acetate (3 x 30mL), the combined organic extracts were dried over magnesium sulfate and concentrated in vacuo, the crude reaction mixture was purified by silica gel chromatography (0% to 60% ethyl acetate/hexanes gradient) to give 1-benzyl-4, 4-dimethyl-pyrrolidin-2-one (834mg, 89%) as a clear oil. ESI-MS M/z calculated 203.13101, Experimental 204.1(M +1) ⁺(ii) a Retention time: 1.3min (LC method B).

Step 2: 1-benzyl-3- (3, 3-dimethylbutyl) -4, 4-dimethyl-pyrrolidin-2-one

A100 mL round-bottom flask was charged with 1-benzyl-4, 4-dimethyl-pyrrolidin-2-one (834mg, 4.103 mmol) and tetrahydrofuran (20mL), andthe reaction flask was purged with nitrogen for 5min, the reaction flask was cooled to-78 ℃, and butyl lithium (2.1mL, 2.5M, 5.250mmol) in hexane was added dropwise, and the mixture was stirred at-78 ℃ for 1h, 1-bromo-3, 3-dimethyl-butane (700 μ L, 4.970mmol) was added dropwise, and the reaction mixture was stirred and slowly warmed to room temperature over a period of 18h, the reaction was quenched with water (10mL) and brine (10mL) and extracted with ethyl acetate (3 x 40mL), the combined organic extracts were dried over magnesium sulfate and concentrated in vacuo, the crude reaction mixture was purified by silica gel chromatography (0% -40% ethyl acetate/hexane gradient) to give 1-benzyl-3- (3, 3-dimethylbutyl) -4, 4-dimethyl-pyrrolidin-2-one (107mg, 9%). ESI-MS calculated M/z 287.2249, Experimental value 288.1(M +1)⁺(ii) a Retention time: 2.15min (LC method B).

And step 3: 3- (3, 3-dimethylbutyl) -4, 4-dimethyl-pyrrolidin-2-one

To a nitrogen purged 50mL flask charged with 1-benzyl-3- (3, 3-dimethylbutyl) -4, 4-dimethyl-pyrrolidin-2-one (107mg, 0.3723 mmol) was added propan-1-amine (3mL) and ethane-1, 2-diamine (200. mu.L, 2.992 mmol). The solution was cooled to-30 ℃ and a lithium wire (4cm, cut into 4 smaller pieces and rinsed with hexanes to remove excess oil) was added. The flask was reassembled with spacers and the reaction mixture was vigorously stirred while warming slightly to-20 deg.C, a blue color eventually formed around the lithium wire, the blue color approximately penetrated into the solution, and the reaction was stirred until the solution remained dark blue (about 20 min). Water (about 15mL) was added and the larger piece of lithium was removed and the mixture was allowed to warm to room temperature and stirred for 10 min. The crude mixture was extracted with ethyl acetate (3 × 20mL), the combined organic extracts were washed with water (15mL), dried over sodium sulfate, filtered and concentrated in vacuo to give crude 3- (3, 3-dimethylbutyl) -4, 4-dimethyl-pyrrolidin-2-one (115mg, 157% (crude product with impurities)) as a yellow oil which was used without further purification ESI-MS m/z calculation 197.17796, realTest value 198.1(M +1)⁺(ii) a Retention time: 1.58min (LC method B).

And 4, step 4: (14S) -8- [3- (3, 3-dimethylbutyl) -4, 4-dimethyl-2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (hydrochloride) (Compound 98)

To a 4mL vial containing crude 3- (3, 3-dimethylbutyl) -4, 4-dimethyl-pyrrolidin-2-one (45mg, 0.2281mmol) was added (14S) -8-chloro-12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (25mg, 0.05373 mmol), (5-diphenylphosphinyl-9, 9-dimethyl-xanthen-4-yl) -diphenyl-phosphine (8mg, 0.01383mmol), tris (dibenzylideneacetone) dipalladium (0) (13mg, 0.01420mmol), cesium carbonate (25mg, 0.07673mmol) and dioxane (1 mL). The headspace was purged with nitrogen, the vial was capped, and the reaction mixture was stirred at 120 ℃ for 18h. The crude residue was dissolved in a minimum amount of dimethylsulfoxide (0.4-1mL) and purified by HPLC (C) ₁₈Reverse phase, 99: 1 to 1: 99 water acetonitrile, hydrochloric acid modifier) the fractions were then concentrated in vacuo and the residue was purified by silica gel chromatography (0% -70%), ethyl acetate/hexane gradient to give (14S) -8- [3- (3, 3-dimethylbutyl) -4, 4-dimethyl-2-oxopyrrolidin-1-yl as an off-white solid]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (hydrochloride) (compound 98) (4mg, 11%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.42(s，1H)，7.66(dd， J＝8.3，3.2Hz，1H) 7.52(ddd, J ═ 22.6, 14.8, 8.2Hz, 2H), 7.03(d, J ═ 7.2Hz, 1H), 6.92(d, J ═ 32.0Hz, 1H), 6.69(d, J ═ 8.7Hz, 1H), 4.46-3.82(m, 3H), 3.83-3.41(m, 3H), 3.09(s, 1H), 2.93(d, J ═ 13.3Hz, 1H), 2.80-2.63(m, 1H), 2.40-2.23(m, 1H), 2.17-1.98(m, 1H), 1.90-1.68(m, 2H), 1.68-1.38(m, 8H), 1.28(d, J ═ 40.1, 5H), 1.18, 6, 6.70H, 1H), 1.02 (d, 1H), 1.9-1H). ESI-MS M/z calculated 610.33014, Experimental 611.2(M +1)⁺(ii) a Retention time: 2.38min (LC method B).

Example 25: preparation of 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ] ]Ethoxy } -1H-pyrazol-1-yl) -18-oxa-2. lambda⁶-thia-3, 9, 11-triazatetracyclo [17.2.2.111, 14.05, 10]Tetracosane-1 (21), 5, 7, 9, 19, 22-hexaen-2, 2, 4-trione (enantiomer 1) (compound 99) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -18-oxa-2. lambda⁶-thia-3, 9, 11-triazatetracyclo [17.2.2.111, 14.05, 10]Tetracosane-1 (21), 5, 7, 9, 19, 22-hexaen-2, 2, 4-trione (enantiomer 2) (compound 100)

Step 1: 2, 2-dimethyl-4- [3- (4-sulfamoylphenoxy) propyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

In a 50mL flask was added 4-hydroxybenzenesulfonamide (471.1mg, 2.720mmol) and N, N-dimethylformamide (13.69mL). Tert-butyl 2, 2-dimethyl-4- (3-methanesulfonyloxypropyl) pyrrolidine-1-carboxylate (912.4mg, 2.720mmol) and potassium carbonate (1.316g, 9.520mmol) were added to the mixture at room temperature and stirred at room temperature for 3h, followed by heating to 50 ℃ overnight, cooling to room temperature and pouring into water (100mL), and extracted with ethyl acetate (2X 100mL), the organic layers were combined, washed with water (2X 100mL),dried (sodium sulfate), filtered and concentrated to a brown residue which was purified by silica gel chromatography using a gradient of 100% hexane to 100% ethyl acetate to give 2, 2-dimethyl-4- [3- (4-sulfamoylphenoxy) propyl as a light orange oil ]Pyrrolidine-1-carboxylic acid tert-butyl ester (578.3mg, 52%).¹H NMR (400MHz, dimethylsulfoxide-d)₆) 7.46(t, J ═ 8.0Hz, 1H), 7.39-7.33(M, 2H), 7.31(s, 2H), 7.13(d, J ═ 7.8Hz, 1H), 4.02(t, J ═ 6.0Hz, 2H), 3.85-3.67(M, 1H), 1.88(dd, J ═ 11.8, 6.6Hz, 2H), 1.79-1.61 (M, 4H), 1.51(dd, J ═ 37.7, 5.8Hz, 2H), 1.38(s, 12H), 1.24(s, 3H), ESI-MS M/z calculated value 412.2032, experimental value 413.3(M +1)⁺(ii) a Retention time: 0.71min (LC method A).

Step 2: 4- [3- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] phenoxy ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

In a 20mL vial, 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (790.2mg, 2.103mmol) and carbonyldiimidazole (341.0mg, 2.103mmol) were combined in tetrahydrofuran (6mL) and stirred loose at 50 ℃ for 120min, then, 2-dimethyl-4- [3- (4-sulfamoylphenoxy) propyl group was added]Pyrrolidine-1-carboxylic acid tert-butyl ester (578.3mg, 1.402mmol) in tetrahydrofuran (10mL) followed by the addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (426.9mg, 419.4 μ L, 2.804 mmol), and the reaction was heated at 50 ℃ for 16 h. The reaction was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution, followed by brine. The organics were separated, dried over sodium sulfate, filtered and evaporated, followed by silica gel chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate, resulting in extremely poor separation. The product containing fractions were combined and concentrated, then re-purified by silica gel chromatography using a gentle gradient of 100% dichloromethane to 20% methanol/dichloromethane, Obtaining 4- [3- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] as a pale yellow solid]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Phenoxy radical]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (953.1mg, 88%). ESI-MS M/z calculated 769.2524, Experimental 770.1(M +1)⁺(ii) a Retention time: 2.49min (LC method B).

And step 3: 2-chloro-N- [4- [3- (5, 5-dimethylpyrrolidin-3-yl) propoxy ] phenyl ] sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide

4- [3- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] group]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Phenoxy radical]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (953.1mg, 1.237mmol) was dissolved in dichloromethane (4.158mL) and trifluoroacetic acid (6.471g, 4.372mL, 56.75mmol) was added to the mixture and the mixture was stirred at room temperature for 60 min. Concentrating the mixture under reduced pressure to dryness, dissolving in saturated aqueous sodium bicarbonate solution and ethyl acetate containing a small amount of methanol to facilitate dissolution and separating the layers, concentrating the organic layer by rotary evaporation, followed by vacuum drying to obtain 2-chloro-N- [4- [3- (5, 5-dimethylpyrrolidin-3-yl) propoxy ] N- [4- [3- (5, 5-dimethylpyrrolidin-3-yl) propoxy ] as an off-white solid ]Phenyl radical]Sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (738.1mg, 89%). ESI-MS M/z calculated 669.19995, Experimental 670.3(M +1)⁺(ii) a Retention time: 0.65min (LC method A).

And 4, step 4: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -18-oxa-2. lambda⁶-thia-3, 9, 11-triazatetracyclo [17.2.2.111, 14.05, 10]Tetracosan-1 (21), 5, 7, 9, 19, 22-hexaen-2, 2, 4-trione (compound 88)

To 2-chloro-N- [4- [3- (5, 5-dimethylpyrrolidin-3-yl) propoxy group]Phenyl radical]Sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]To a solution of pyridine-3-carboxamide (738.1mg, 1.101mmol) in dimethyl sulfoxide (29.52mL) were added potassium carbonate (912.8mg, 6.605mmol), cesium fluoride (200.7mg, 1.321mmol) and a small amount

The resulting mixture was capped and heated to 130 ℃ for 16 h-heating was continued at 150 ℃ for 16h. Heating to 170 ℃ and stirring for 3h, followed by cooling to room temperature, dilution with ethyl acetate and washing with saturated aqueous ammonium chloride solution and brine the organic phase was dried (sodium sulfate), filtered and concentrated to a brown amorphous solid which was purified by silica gel chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate to give 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl acetate as a white solid ]Ethoxy } -1H-pyrazol-1-yl) -18-oxa-2. lambda⁶-thia-3, 9, 11-triazatetracyclo [17.2.2.111, 14.05, 10]Tetracosan-1 (21), 5, 7, 9, 19, 22-hexaen-2, 2, 4-trione (30mg, 4%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.13(s, 1H), 8.17(d, J ═ 2.8Hz, 1H), 8.06(d, J ═ 7.8Hz, 1H), 7.83(d, J ═ 8.3Hz, 1H), 7.78(d, J ═ 8.6Hz, 1H), 7.30(dd, J ═ 8.8, 2.4Hz, 1H), 7.19(dd, J ═ 8.6, 2.4Hz, 1H), 6.89(d, J ═ 8.3Hz, 1H), 6.10(d, J ═ 2.7Hz, 1H), 4.52(d, J ═ 12.1Hz, 1H), 4.30(t, J ═ 7.0Hz, 2H), 4.27-4.17(m, 1H), 2.07(t, J ═ 7, 1H), 2.0 (s, 1H), 1H), 4.50 (s, 1H), 1H), 4.0 (t, J ═ 7, 2.0H, 2.0 (s, 1H), 1H), 4.8, 1H, 6.8, 1H, 6(s, 1H), 4.0 (s, 6, 1H), 4.0, 6, 1H), 4.0 (H), 4.8, 1H, 6, 1, 2H) in that respect ESI-MS M/z calculated 633.22327, Experimental 634.1(M +1)⁺(ii) a Retention time: 2.28min (LC method B).

And 5: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -18-oxa-2. lambda⁶-thia-3, 9, 11-triazatetracyclo [17.2.2.111, 14.05, 10]Tetracos-1 (21), 5, 7, 9, 19, 22-hexaene -2, 2, 4-trione (enantiomer 1) (compound 99) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -18-oxa-2. lambda⁶-thia-3, 9, 11-triazatetracyclo [17.2.2.111, 14.05, 10]Tetracosane-1 (21), 5, 7, 9, 19, 22-hexaen-2, 2, 4-trione (enantiomer 2) (compound 100)

Racemic 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] 8, 12-dimethyl by SFC chromatography using ChiralCel OD-H (250 × 10mm column, 5 μm particle size) and a 42% acetonitrile/methanol (90: 10)/58% carbon dioxide mobile phase (10mL/min over 8.0min) (infusion volume 70 μ L24 mg/mL solution in acetonitrile/methanol (90: 10))]Ethoxy } -1H-pyrazol-1-yl) -18-oxa-2. lambda⁶-thia-3, 9, 11-triazatetracyclo [17.2.2.111, 14.05, 10]The tetracosane-1 (21), 5, 7, 9, 19, 22-hexaen-2, 2, 4-trione (27.2mg, 0.04292 mmol) was subjected to chiral separation to give 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] ketone as the first enantiomer to be eluted as a white solid]Ethoxy } -1H-pyrazol-1-yl) -18-oxa-2. lambda⁶-thia-3, 9, 11-triazatetracyclo [17.2.2.111, 14.05, 10]Tetracosan-1 (21), 5, 7, 9, 19, 22-hexaen-2, 2, 4-trione (enantiomer 1) (compound 99) (10.22mg, 75%); ¹H NMR (400MHz, dimethylsulfoxide-d)₆) 12.13(s, 1H), 8.17(d, J ═ 2.8Hz, 1H), 8.07(d, J ═ 8.4Hz, 1H), 7.83(d, J ═ 8.3Hz, 1H), 7.79(d, J ═ 8.8Hz, 1H), 7.31(dd, J ═ 8.8, 2.5Hz, 1H), 7.20(dd, J ═ 8.6, 2.4Hz, 1H), 6.90(d, J ═ 8.3Hz, 1H), 6.10(d, J ═ 2.8Hz, 1H), 4.52(d, J ═ 11.9Hz, 1H), 4.30 (t, J ═ 7.1Hz, 2H), 4.26-4.16(m, 1H), 2.07(t, 7.92, J ═ 1.9Hz, 1H), 1H, 4.8H, 1H, 7.8H, 1H, 8H, 1H, 7.8H, 1H, 8H, 1H, 3H, 1H, 2H) 0.89(d, J ═ 11.6Hz, 2H), calculated ESI-MS M/z 633.22327, experimental 634.1(M +)1)⁺(ii) a Retention time: 2.25min (LC method B) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid as the second enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -18-oxa-2. lambda⁶-thia-3, 9, 11-triazatetracyclo [17.2.2.111, 14.05, 10]Tetracosan-1 (21), 5, 7, 9, 19, 22-hexaen-2, 2, 4-trione (enantiomer 2) (compound 100) (9.72mg, 71%); ESI-MS M/z calculated 633.22327, Experimental 634.1(M +1) ⁺(ii) a Retention time: 2.25min (LC method B).

Example 26: preparation of (14S) -8- [3- (4, 4-dimethylpentyl) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 102)

Step 1: 3- (4, 4-dimethylpentyl) pyrrolidin-2-one

To a solution of pyrrolidin-2-one (4.64g, 54.52mmol) in anhydrous tetrahydrofuran (300mL) was added dropwise a 2.5M n-butyllithium solution/hexane (43.6mL, 0.109mol) at-78 deg.C, and the reaction solution was stirred at this temperature for 1 h. A solution of 1-chloro-4, 4-dimethylpentane (7.34g, 54.52mmol) in dry tetrahydrofuran (20mL) was added slowly. After the addition was complete, the solution was stirred at-78 ℃ for 20min, after which it was gradually warmed to ambient temperature. 20% aqueous ammonium chloride (100mL) was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3 × 150mL) and the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated the obtained residue was purified by silica gel column chromatography using a 0-100% ethyl acetate/hexane gradient to give 3- (4, 4-dimethylpentyl) pyrrolidin-2-one as a white solid (3.86g, 39%). ¹H NMR(250MHz，CDCl₃) (ppm): 7.51(s, 1H), 3.12(m, 2H), 2.15(m, 2H), 1.60(m, 2H), 1.29-1.11(m, 5H), 0.86(s, 9H). ESI-MS M/z calculated 183.16, Experimental 184.2(M +1)⁺Retention time: 4.66min (LC method Q).

Step 2: (14S) -8- [3- (4, 4-dimethylpentyl) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 102)

A4 mL vial was charged with (14S) -8-chloro-12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (25mg, 0.05373 mmol), 3- (4, 4-dimethylpentyl) pyrrolidin-2-one (29mg, 0.1582mmol) (crude, unknown purity), Pd₂(dba)₃(10mg, 0.01092mmol), xanthphos (6mg, 0.01037mmol), cesium carbonate (87.52 mg, 0.2686mmol) and anhydrous dioxane (0.4 mL). The mixture was aerated with nitrogen for 1-2min, capped and stirred at 120 ℃ for 21 h. The reaction was diluted with dimethylsulfoxide (700 μ L), microfiltered and subjected to reverse phase preparative HPLC (C) using a gradient of acetonitrile in water (1 to 99% over 15min) and hydrochloric acid as modifier ₁₈) The pure fractions were collected, a small amount of brine was added and the organic solvent was evaporated. Evaporation of the solvent gave 8mg of solid the product was purified by flash chromatography on silica gel (4g column) using a gradient of methanol/dichloromethane (0 to 5% over 30 min.) the pure fractions were collected and the solvent was evaporated to give a mixture of diastereomers as a white solid, i.e. (14S) -8- [3- (4, 4-dimethylpentyl) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 102) (5.5mg，17％)。¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.42(s, 1H), 7.68(d, J ═ 8.5Hz, 1H), 7.61-7.48(M, 2H), 7.04(d, J ═ 7.1Hz, 1H), 6.96 (width s, 1H), 6.70(d, J ═ 8.5Hz, 1H), 4.08-3.72(M, 3H), 3.10(br d, J ═ 8.8Hz, 1H), 2.94(d, J ═ 13.2Hz, 1H), 2.74-2.60 (M, 2H), 2.33-2.18(M, 1H), 2.10(br s, 1H), 1.86-1.66(M, 4H), 1.65-1.44(M, 9H), 1.37-1.15(M, 6H), 0.87(d, J ═ 8, 8H, 1H), 1.83 (M, 6H), calculated values of M, 2H, 18(M, 3H), 1H), 1.84 (M, 3H), calculated values of M, 3H) ⁺(ii) a Retention time: 2.29min (LC method B).

Example 27: synthesis of 8- [3- ({ dispiro [2.0.2.1 ]]Hept-7-yl } methoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 1) (compound 106) and 8- [3- ({ dispiro [2.0.2.1 ]]Hept-7-yl } methoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 2) (compound 107)

Step 1: 1-cyclopropyl propanol

To a solution of methyl cyclopropanecarboxylate (75g, 749.1mmol) in ether (450mL) was added titanium (IV) isopropoxide (55.3mL, 187.4 mmol.) Ethylmagnesium bromide (1.6L, 1M, 1.60mol) was slowly added to the mixture over 2 h. The addition is exothermic and is controlled by monitoring the rate of addition and using a cooling bath the reaction temperature is maintained between 21 ℃ and 26 ℃ during the addition. After addition, the mixture was stirred at ambient temperature for a further 2 h. Next, the mixture was cooled to-5 ℃ using an acetone/dry ice bath and sulfuric acid (97) 0g, 10% w/w, 990mmol) was slowly quenched. The reaction mixture was cooled in a dry ice/acetone bath to maintain the reaction vessel below 0 ℃ during quenching. As the quench proceeded, a grey/purple solid formed, after complete addition of aqueous sulfuric acid, the mixture was stirred at 0 ℃ for 1 h. The precipitate was filtered through celite using a medium pore glass frit and washed with diethyl ether (900 mL.) the filtrate was transferred to a separatory funnel and the organic phase was washed with brine (1L), saturated sodium bicarbonate (1L) and brine (1L). The organic phase was dried over magnesium sulfate, filtered over celite and the solvent was evaporated by rotary evaporation at 100 torr and the water bath was set to 20 ℃. The crude product was stored at-23 ℃ overnight and used without further purification the product 1-cyclopropylcyclopropyl cyclopropanol (61g, 83%) was found to contain about 50% solvent (tetrahydrofuran and diethyl ether)ⁱPrOH) and used as such in the next step.¹H NMR (400MHz, chloroform-d) 1.32(tt, J ═ 8.2, 5.1Hz, 1H), 0.71-0.61(m, 2H), 0.51-0.43(m, 2H), 0.43-0.33(m, 2H), 0.23-0.14(m, 2H).

Step 2: 1-bromo-1-cyclopropyl-cyclopropane

A solution of triphenylphosphine (56.1g, 213.9mmol) in dichloromethane (200mL) was cooled to-10 ℃, a solution of bromine (11.0mL, 214mmol) in dichloromethane (40mL) was added and the reaction was stirred at-10 ℃ for a further 15min, then the reaction was cooled to-30 ℃ and pyridine (3.3mL, 41mmol) was added, a solution of 1-cyclopropylcyclopropanol (20.0g, 204mmol), pyridine (17.3mL, 214mmol) and dichloromethane (100mL) was added dropwise while maintaining the temperature between-15 ℃ and-20 ℃, after 30min the addition was complete and the reaction was allowed to gradually warm to room temperature. The organic phase was washed successively with 1M hydrochloric acid (102mL), followed by saturated sodium bicarbonate (50mL), dried over sodium sulfate, filtered and concentrated (30 ℃/indoor at about 300 torr) to remove most of the dichloromethane . The crude reaction mixture was flashed (40 ℃/20 torr) to further remove the dichloromethane the solid residue (Ph3PO and product) was reheated and distilled (50 to 60 ℃/20 torr) to give 21.5g (65% yield) of 1-bromo-1-cyclopropyl-cyclopropane as a cloudy colourless liquid.¹H NMR (400MHz, chloroform-d) 1.61(tt, J ═ 8.2, 5.0Hz, 1H), 1.07-1.02(m, 2H), 0.78-0.66(m, 2H), 0.67-0.51(m, 2H), 0.35-0.21(m, 2H).

And step 3: cyclopropylidene cyclopropane

A solution of potassium tert-butoxide (16.7g, 148.8mmol) in dimethyl sulfoxide (100mL) was stirred at room temperature in a 3-neck 250-mL round-bottom flask. 1-bromo-1-cyclopropyl-cyclopropane (20.0g, 124.2mmol) was added dropwise and the reaction immediately turned dark and then brown. The reaction was slightly exothermic (temperature was maintained between 18 ℃ and 22 ℃ using an ice water bath.) after 10min, the addition was complete. The ice water bath was removed and the reaction was stirred at room temperature. After 90min, the reaction mixture was distilled under vacuum using bulb-to-bulb distillation (bulb-to-bulb distillation) the distillation occurred between 60 ℃ to 80 ℃ and 40 and 100 torr. The distillate was slowly collected in a receiver to give 18.2g of a colourless liquid (7.3g of product as a 42% by weight solution in tert-butanol). The distillate was further washed with water (5X 10 mL) dichloromethane (4g) was added and the mixture was dried over magnesium sulfate, filtered (washed with 2 additional portions of 3g dichloromethane each) to give 17.30g of a colourless liquid (6.9g product as a 39.6 wt% solution in dichloromethane; 69% yield). ¹H NMR (400MHz, chloroform-d) 1.19(s, 8H).¹H NMR confirmed the presence of methylene chloride and a small amount of t-butanol.

And 4, step 4: dispiro [2.0.2.1] heptane-7-carboxylic acid ethyl ester

To cyclopropylene cyclopropane (49.5g, 617.8mmol) in dichloro at 0 ℃ under a nitrogen atmosphereRhodium (II) acetate (4.2g, 9.503mmol) was added to a solution in methane (110 mL.) to the mixture was added 2-diazoacetic acid ethyl ester (106.8mL, 1.016mol) at 0 ℃ using a syringe pump set to an addition rate of 0.02mL/min (1.2 mL/h). The addition was continued for 89 hours the crude reaction mixture was filtered through a silica plug, washed 3 times with 150mL each of dichloromethane and the volatiles removed in vacuo to give a crude dark yellow oil, dispiro [2.0.2.1]]Ethyl heptane-7-carboxylate (100g, 97% containing about 20% dichloromethane, (E) -diethyl but-2-enedioate and (Z) -diethyl but-2-enedioate in the form of a mixture) was used directly in the next step.¹H NMR (400MHz, chloroform-d) 4.13(q, J ═ 7.1Hz, 2H), 2.23(s, 1H), 1.24(t, J ═ 7.1Hz, 3H), 1.08-0.93(m, 4H), 0.90-0.82(m, 2H), 0.77(ddd, J ═ 8.2, 5.0, 3.5Hz, 2H).

And 5: disospiro [2.0.2.1] hept-7-ylmethanols

To a slurry of lithium aluminum hydride (7.8g, 200.2mmol) in diethyl ether (300mL) cooled with an ice-water bath was slowly added dispiro [2.0.2.1] heptane-7-carboxylic acid ethyl ester (10.77g, 64.79mmol) during the addition the mixture was warmed to slight reflux and stirring continued at ambient temperature for 1 h. The reaction was cooled with an ice-water bath and quenched slowly by adding water (8.0mL, 440mmol), followed by sodium hydroxide (8.0mL, 2M, 16mmol), followed by water (24.0mL, 1.33 mol). The pale yellow slurry was filtered through celite and washed 3 times with 150mL of methyl tert-butyl ether. The filtrate was concentrated in vacuo to give 8.87g of a clear oil, dispiro [2.0.2.1] hept-7-ylmethanol (8.87g, quantitative yield).

¹H NMR (400MHz, chloroform-d) 3.71(dd, J ═ 6.7, 5.5Hz, 2H), 1.76 to 1.65(m, 1H), 1.46(t, J ═ 5.6Hz, 1H), 0.87(q, J ═ 1.9Hz, 4H), 0.72 to 0.61(m, 2H), 0.60 to 0.50(m, 2H).

Step 6: 3- (Dispiro [2.0.2.1] hept-7-ylmethoxy) -1H-pyrazole-1-carboxylic acid tert-butyl ester

Dispiro [2.0.2.1] cooled in an ice bath]Hept-7-ylmethanol (1.36g, 11.0mmol), a solution of tert-butyl 3-hydroxypyrazole-1-carboxylate (2.3g, 12mmol) and triphenylphosphine (3.2g, 12mmol) in tetrahydrofuran (28mL) and diisopropyl azodicarboxylate (2.4mL, 12mmol) was added slowly, the cooling bath was removed and the reaction stirred for 15h, the reaction was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate, filtered and evaporated in vacuo the residue was purified by silica gel chromatography eluting with a gradient of 0-20% ethyl acetate/hexane to give 3- (dispiro [2.0.2.1] 2.0.2.1 as a colorless oil]Hept-7-ylmethoxy) -1H-pyrazole-1-carboxylic acid tert-butyl ester (1.57g, 49% yield). ESI-MS M/z calculated 290.16306, Experimental 291.3 (M +1)⁺(ii) a Retention time: 0.76min (LC method A).

And 7: 3- (dispiro [2.0.2.1] hept-7-ylmethoxy) -1H-pyrazole

Reacting 3- (dispiro [2.0.2.1] ]A solution of hept-7-ylmethoxy) -1H-pyrazole-1-carboxylic acid tert-butyl ester (1.57g, 5.41mmol) and trifluoroacetic acid (2.2mL, 29mmol) in dichloromethane (20mL) was stirred for three hours the volatiles were removed in vacuo and the residue was basified with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate the combined extracts were dried over sodium sulfate, filtered and evaporated to give 3- (dispiro [2.0.2.1] as a pale yellow oil]Hept-7-ylmethoxy) -1H-pyrazole (0.94g, 91% yield). ESI-MS M/z calculated 190.11061, Experimental 191.1(M +1)⁺(ii) a Retention time: 0.52min (LC method A).

And 8: 2-chloro-6- (3- (dispiro [2.0.2.1] hept-7-ylmethoxy) -1H-pyrazol-1-yl) nicotinic acid ethyl ester

Stirring 3- (dispiro [2.0.2.1]]Hept-7-ylmethoxy) -1H-pyrazole (0.94g, 4.9mmol), ethyl 2, 6-dichloropyridine-3-carboxylate (1.15g, 5.23mmol), potassium carbonate (0.83g, 6.0mmol) and 1, 4-diazabicyclo [2.2.2 mmol]A mixture of octane (0.12g, 1.1mmol) in dimethyl sulfoxide (16mL) for 24h, the reaction was diluted with water and extracted with ethyl acetate, the combined extracts were washed with brine and water, dried over sodium sulfate, filtered and evaporated in vacuo, the residue was purified by silica gel column chromatography eluting with a gradient of 0-20% ethyl acetate/hexane to give 2-chloro-6- (3- (dispiro [2.0.2.1] as a colorless solid ]Hept-7-ylmethoxy) -1H-pyrazol-1-yl) nicotinic acid ethyl ester (1.39g, 75% yield).¹H NMR (400MHz, chloroform-d) 8.36(d, J ═ 2.8Hz, 1H), 8.27 (d, J ═ 8.5Hz, 1H), 7.72(d, J ═ 8.5Hz, 1H), 5.96(d, J ═ 2.9Hz, 1H), 4.41(q, J ═ 7.1Hz, 2H), 4.30(d, J ═ 7.0Hz, 2H), 1.94(t, J ═ 7.0Hz, 1H), 1.42(t, J ═ 7.1Hz, 3H), 1.02-0.89(M, 4H), 0.75-0.65(M, 2H), 0.65-0.53(M, 2H), ESI-MS M/z calculated value 373.11932, experimental value 374.2(M + 1H)⁺(ii) a Retention time: 0.87min (LC method A).

And step 9: 2-chloro-6- [3- (dispiro [2.0.2.1] hept-7-ylmethoxy) pyrazol-1-yl ] pyridine-3-carboxylic acid

Stirring of 2-chloro-6- (3- (dispiro [2.0.2.1]]Hept-7-ylmethoxy) -1H-pyrazol-1-yl) nicotinic acid ethyl ester (1.39g, 3.72mmol) and sodium hydroxide (7.5mL of a 1M solution, 7.5mmol) in tetrahydrofuran (6mL) and ethanol (3 mL) for 90 min. The volatiles were removed in vacuo and water was added the reaction was cooled in an ice bath and hydrochloric acid (7.5mL of a 1M solution, 7.5mmol) was added slowly. The reaction was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give 2-chloro-6- [3- (dispiro [2.0.2.1] as a colorless solid ]Hept-7-ylmethoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (1.16g, 82% yield).¹H NMR (400MHz, dimethylsulfoxide-d)₆)8.41(d，J＝2.9Hz，1H)，8.38(d，J＝8.4Hz，1H) 7.73(d, J ═ 8.4Hz, 1H), 6.19(d, J ═ 2.8Hz, 1H), 4.27(d, J ═ 7.0Hz, 2H), 1.93(t, J ═ 7.0Hz, 1H), 0.97-0.79(m, 4H), 0.76-0.66(m, 2H), 0.65-0.56(m, 2H). ESI-MS M/z calculated 345.088, Experimental 346.1(M +1)⁺(ii) a Retention time: 0.73min (LC method A).

Step 10: 4- [3- [ [6- [ [ 2-chloro-6- [3- (dispiro [2.0.2.1] hept-7-ylmethoxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

A100 mL flask was charged with 2-chloro-6- [3- (dispiro [2.0.2.1] under nitrogen]Hept-7-ylmethoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (300mg, 0.8676mmol) and anhydrous tetrahydrofuran (4 mL). Add carbonyldiimidazole (214mg, 1.320mmol) and stir the mixture at room temperature under nitrogen for 2h in a separate 20mL vial maintained under nitrogen to prepare 2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (358mg, 0.8678mmol) in anhydrous tetrahydrofuran (2mL) and added to the activated ester solution by syringe 1, 8-diazabicyclo [5.4.0 ] was added ]Undec-7-ene (0.29 mL, 1.939mmol) and the mixture was stirred at room temperature for 19 h. The solvent was evaporated and the residue was treated with water (50mL), ethyl acetate (50mL) and hydrochloric acid (1mL, 6M, 6.000mmol) the two phases were separated, the aqueous phase was further extracted with ethyl acetate (25mL), the combined organics were washed with brine (30mL), dried over sodium sulfate and the solvent was evaporated, the product was dissolved in dichloromethane and purified by flash chromatography on silica gel using a gradient of ethyl acetate/hexane (0 to 100% over 30 min). The pure fractions were collected and the solvent was evaporated, yielding 408mg of product as a foamy solid. LCMS showed that this material contained 6% of the starting carboxylic acid. The product was purified a second time using the same procedure to give 4- [3- [ [6- [ [ 2-chloro-6- [3- (dispiro [2.0.2.1 ]) as a colorless resin]Hept-7-ylmethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester(364mg, 57%). ESI-MS M/z calculated 739.2919, Experimental 740.3(M +1)⁺(ii) a Retention time: 2.45min (LC method B).

Step 11: 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-3-yl) propylamino ] -2-pyridinyl ] sulfonyl ] -6- [3- (dispiro [2.0.2.1] hept-7-ylmethoxy) pyrazol-1-yl ] pyridine-3-carboxamide (dihydrochloride)

A100 mL round bottom flask was charged with 4- [3- [ [6- [ [ 2-chloro-6- [3- (dispiro [2.0.2.1 ]]Hept-7-ylmethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (364mg, 0.4917mmol), dichloromethane (5mL) and hydrochloric acid (0.5mL, 4M, 2.000mmol) (4M in dioxane.) the vial was capped and stirred at room temperature for 5 h. Additional amount of hydrochloric acid (0.5mL, 4M, 2.000mmol) was added and the mixture was stirred for an additional 1 hour. This procedure was repeated until a white solid was obtained vacuum drying to give 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-3-yl) propylamino ] as a white solid]-2-pyridyl]Sulfonyl radical]-6- [3- (dispiro [2.0.2.1 ]]Hept-7-ylmethoxy) pyrazol-1-yl]Pyridine-3-carboxamide (dihydrochloride) (325mg, 93%). ESI-MS M/z calculated 639.23944, Experimental 640.3 (M +1)⁺(ii) a Retention time: 1.58min (LC method B).

Step 12: 8- [3- ({ dispiro [2.0.2.1 ]]Hept-7-yl } methoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 1) (compound 106) and 8- [3- ({ dispiro [2.0.2.1 ]]Hept-7-yl } methoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 2) (compound 107)

A100 mL round bottom flask equipped with a magnetic stir bar was charged under nitrogen with 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-3-yl) propylamino]-2-pyridyl]Sulfonyl radical]-6- [3- (dispiro [2.0.2.1 ]]Hept-7-ylmethoxy) pyrazol-1-yl]Pyridine-3-carboxamide (dihydrochloride) (325mg, 0.4557mmol), anhydrous NMP (3 mL), potassium carbonate (269mg, 1.946mmol) (freshly milled in a mortar) and cesium fluoride (70mg, 0.4608 mmol). the mixture was stirred vigorously under nitrogen at 140 ℃ for 15h, the mixture was diluted with water (20mL) and acidified (500 μ L, 6M, 3.000mmol, final pH 4-5) by slow addition of hydrochloric acid, the resulting solid was filtered and air dried approximately, the solid was dissolved in dichloromethane/ethyl acetate (75 mL total volume), dried over sodium sulfate, filtered and concentrated to give a solution which was purified by flash chromatography on silica gel using a gradient of methanol/dichloromethane (0 to 5% over 30 min). Evaporation of the solvent gave racemic 8- [3- ({ dispiro [2.0.2.1 ] ]Hept-7-yl } methoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 105) (102mg, 36%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.51(s, 1H), 8.20(d, J ═ 2.8Hz, 1H), 7.81(d, J ═ 8.2Hz, 1H), 7.58(dd, J ═ 8.5, 7.2Hz, 1H), 7.05 (width d, J ═ 7.2Hz, 1H), 6.97(s, 1H), 6.92(d, J ═ 8.2Hz, 1H), 6.71(d, J ═ 8.5Hz, 1H), 6.11(d, J ═ 2.7Hz, 1H), 4.24(d, J ═ 7.0Hz, 2H), 4.0-3.85(m, 1H), 3.15(br s, 1H), 2.95(br d, J ═ 13.3Hz, 1H), 2.65-2.75 (m, 1H), 1H, 7.75 (t, 1H), 1H, 7.7.7H, 1H), 7.7.7H, 1H, 7H, 1H, 7H, 1H, 7H, 1H, 7H, 1H, 0.66-0.53(M, 2H). ESI-MS M/z calculated 603.26276, Experimental 604.2 (M +1)⁺(ii) a Retention time: 2.26min (LC method B.) chiral SFC separation (ChiralPak column AS-H (250X 10.) of this racemic material (97mg)mm), 5 μm, 35 ℃, mobile phase 38% acetonitrile: methanol (90: 10, without modifier), 62% carbon dioxide, 10mL/min, 24mg/mL in acetonitrile: methanol (90: 10, without modifier), injection volume 70 μ L, 100 bar) ]Hept-7-yl } methoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 1) (compound 106) (46mg, 32%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.50(s, 1H), 8.20(d, J ═ 2.8Hz, 1H), 7.81(d, J ═ 8.2Hz, 1H), 7.57(t, J ═ 7.8Hz, 1H), 7.05(d, J ═ 7.2Hz, 1H), 6.98 (wide d, J ═ 7.3Hz, 1H), 6.91(d, J ═ 8.2Hz, 1H), 6.71(d, J ═ 8.5Hz, 1H), 6.10(d, J ═ 2.7Hz, 1H), 4.23(d, J ═ 7.0Hz, 2H), 3.99-3.82(m, 1H), 3.15 (brs, 1H), 2.95 (brd, J ═ 13.4, 1H), 2.80-2.81H), 2.62-3.81 (m, 1H), 1H, 9.68 (t, 1H, 9H, 1, 2H) 0.66-0.53(M, 2H). ESI-MS M/z calculated 603.26276, Experimental 604.3(M +1)⁺(ii) a Retention time: 2.27min (LC method E). The second enantiomer to be eluted was collected and the solvent was evaporated and the residue triturated in dichloromethane/hexane. Evaporation to give 8- [3- ({ dispiro [2.0.2.1 ] ]Hept-7-yl } methoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 2) (compound 107) (43mg, 31%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.50(s, 1H), 8.20(d, J ═ 2.8Hz, 1H), 7.81(d, J ═ 8.2Hz, 1H), 7.57(t, J ═ 7.9Hz, 1H), 7.05 (d, J ═ 7.2Hz, 1H), 6.98 (wide d, J ═ 8.5Hz, 1H), 6.91(d, J ═ 8.2Hz, 1H), 6.71(d, J ═ 8.5Hz, 1H), 6.10(d, J ═ 2.7Hz, 1H), 4.23(d, J ═ 7.0Hz, 2H), 4.02-3.82(m, 1H), 3.23-3.06(m, 1H), 2.95(br d, J ═ 13.1H),1H) 2.80-2.62(m, 1H), 2.12(br s, 1H), 1.91(t, J ═ 7.0Hz, 1H), 1.88-1.68(m, 2H), 1.68-1.42(m, 9H), 1.39-1.24(m, 1H), 0.96-0.81(m, 4H), 0.74-0.64(m, 2H), 0.64-0.53(m, 2H). ESI-MS M/z calculated 603.26276, Experimental 604.3(M +1)⁺(ii) a Retention time: 2.27min (LC method B).

Example 28: preparation of 12, 12, 20-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 114) and 12, 12, 20-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 115)

Step 1: 2-chloro-6-iodo-3-methyl-pyridine

A solution of 2- (dimethylamino) ethanol (13.02g, 14.7mL, 146.1mmol) in hexane (120mL) was cooled to-5 deg.C and treated with butyllithium (132mL of 2.5M in hexane, 330.0mmol) over a period of 45 min. The flask was maintained between-5 ℃ and 0 ℃ for 1h and then cooled to-78 ℃. A solution of 2-chloro-3-methyl-pyridine (7g, 54.87mmol) in hexane (70mL +10mL rinse) was added dropwise during 30min and the mixture was stirred at-78 ℃ for 2 h. A solution of iodine (56g, 11.36mL, 220.6 mmol) in tetrahydrofuran (200mL) was added dropwise over a period of about 1h and the reaction mixture was allowed to gradually warm to room temperature overnight. The mixture was cooled in an ice bath and quenched slowly with water (250 mL). Transfer to a 1000mL separatory funnel and separate the layers. Using ethyl acetate (2 in a recovery area) 250mL) and the organic layers were combined, washed with water containing 10% aqueous sodium thiosulfate (the organic layer became clear), washed with water (200mL) and brine (200 mL). The residue was purified by 220g silica gel column chromatography, eluting from 0% to 15% ethyl acetate/heptane, to give pure and mixed fractions. The combined fractions were further purified by 120g silica gel column chromatography eluting from 0% to 15% ethyl acetate/heptane, then triturated in heptane, dried and combined to the previous pure fraction from the first silica gel column to give 2-chloro-6-iodo-3-methyl-pyridine as a pale yellow solid (9.7g, 68%).¹H NMR(300MHz，CDCl₃) ppm 2.32(s, 3H), 7.18(d, J ═ 7.6Hz, 1H), 7.56(d, J ═ 7.6Hz, 1H), ESI-MS M/z calculated 252.9155, experimental 254.0(M +1)⁺(ii) a Retention time: 2.71min (LC method H).

Step 2: 3- [ (6-chloro-5-methyl-2-pyridyl) sulfanyl ] propionic acid 2-ethylhexyl ester

A solution of 2-chloro-6-iodo-3-methyl-pyridine (15.4g, 60.76mmol) and diisopropylethylamine (15.73g, 21.2mL, 121.7mmol) in toluene (300mL) was degassed by bubbling nitrogen for 10 min.Tri (dibenzylideneacetone) dipalladium (0) (1.7g, 1.856mmol), Xantphos (2.1g, 3.629mmol) and 2-ethylhexyl 3-sulfanylpropionate (14.6g, 66.86mmol) were added and the mixture was heated at 110 deg.C overnight, the residue was concentrated under reduced pressure and purified by column chromatography on 220g column eluting from 0% to 20% ethyl acetate/heptane to give 3- [ (6-chloro-5-methyl-2-pyridinyl) sulfanyl) sulfanylpyridin as a yellow oil ]2-ethylhexyl propionate (15.8g, 76%).¹H NMR(300MHz，CDCl₃) ppm 0.88(t, J ═ 7.3Hz, 6H), 1.20-1.44(M, 9H), 2.30(s, 3H), 2.77(t, J ═ 7.0Hz, 2H), 3.40(t, J ═ 6.9Hz, 2H), 3.97-4.06(M, 2H), 7.00(d, J ═ 7.9Hz, 1H), 7.33(d, J ═ 7.9Hz, 1H), ESI-MS M/z calculated value 343.912, experimental value 344.2(M +1)⁺(ii) a RetentionTime: 2.76min (LC method I).

And step 3: 3- [ (6-chloro-5-methyl-2-pyridyl) sulfonyl ] propionic acid 2-ethylhexyl ester

Para-chloroperbenzoic acid (21.6g, 96.38mmol) was slowly added to 3- [ (6-chloro-5-methyl-2-pyridyl) sulfanyl at room temperature]A solution of 2-ethylhexyl propionate (15.8g, 45.94mmol) in dichloromethane (135 mL). The mixture was stirred at this temperature for 5 h. Ethyl acetate (500mL) was added and the resulting mixture was washed with a saturated solution of sodium bicarbonate (250mL), followed by 0.5M sodium hydroxide solution (2X 250 mL.) the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting from 0% to 40% ethyl acetate/heptane on a 220g column to give 3- [ (6-chloro-5-methyl-2-pyridinyl) sulfonyl as a clear oil]2-ethylhexyl propionate (12.36g, 72%).¹H NMR(300MHz，CDCl₃) ppm 0.82-0.94(M, 6H), 1.20-1.41(M, 9H), 2.49(s, 3H), 2.78-2.89(M, 2H), 3.66-3.76(M, 2H), 4.01(dd, J ═ 6.0, 1.9Hz, 2H), 7.77-7.84(M, 1H), 7.89-7.96(M, 1H), ESI-MS M/z calculated 375.911, experimental 376.1(M +1) ⁺(ii) a Retention time: 2.43min (LC method I).

And 4, step 4: 6-chloro-5-methyl-pyridine-2-sulfonamide

Sodium methoxide (7.1g, 131.4mmol) was added to 3- [ (6-chloro-5-methyl-2-pyridyl) sulfonyl group at room temperature]A solution of 2-ethylhexyl propionate (12.36g, 32.88mmol) in tetrahydrofuran (100mL) and methanol (35mL) the reaction mixture was stirred for 4h, then the mixture was concentrated under reduced pressure to give the intermediate as a white solid. To this intermediate was added an aqueous solution (240mL) of hydroxylamine-O-sulfonic acid (7.4g, 65.43mmol) and sodium acetate (8.1g, 98.74mmol) at 0 deg.CmL) was extracted. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel on a 120g column eluting from 20% to 80% ethyl acetate/heptane to give 6-chloro-5-methyl-pyridine-2-sulfonamide as a white solid (5.9g, 86%).¹H NMR (300MHz, dimethylsulfoxide-d)₆) ppm 2.40(s, 3H), 7.59(s, 2H), 7.82(d, J ═ 7.6Hz, 1H), 8.04(d, J ═ 7.6Hz, 1H). ESI-MS M/z calculated 206.65, Experimental 207.1(M +1)⁺(ii) a Retention time: 1.44min (LC method I).

And 5: tert-butyl 2, 2-dimethyl-4- [3- [ (3-methyl-6-sulfamoyl-2-pyridyl) amino ] propyl ] pyrrolidine-1-carboxylate:

In a 5mL microwave vial, 6-chloro-5-methyl-pyridine-2-sulfonamide (460mg, 2.226mmol), tert-butyl 4- (3-aminopropyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (380mg, 1.482mmol), and diisopropylethylamine (1.3mL, 7.463mmol) were dissolved in n-butanol (3mL), the vial was sealed and stirred at 160 ℃ overnight. The mixture was filtered and purified by preparative reverse phase HPLC (C)₁₈): gradient of 1-99% acetonitrile in water/hydrochloric acid modifier (15min) to obtain 2, 2-dimethyl-4- [3- [ (3-methyl-6-sulfamoyl-2-pyridyl) amino]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (130mg, 21%). ESI-MS M/z calculated 426.23007, Experimental 427.36(M +1)⁺(ii) a Retention time: 1.36min (LC method B).

Step 6: 4- [3- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -3-methyl-2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester:

in a 20mL microwave vial, 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (345mg, 0.9182mmol) and carbonyldiimidazole (150mg, 0.9251mmol) were evacuated/backfilled with nitrogen (3 times). Anhydrous tetrahydrofuran (4mL) was added and the mixture was stirred at 50 ℃ for 90min, next, 2-dimethyl-4- [3- [ (3-methyl-6-sulfamoyl-2-pyridyl) amino group was added ]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (260mg, 0.6095mmol) and 1, 8-diazabicyclo [5.4.0]A solution of undec-7-ene (228 μ L, 1.525mmol) in tetrahydrofuran (4mL) and the mixture stirred at 50 ℃ overnight, the reaction was diluted with ethyl acetate and washed with 1M aqueous citric acid followed by brine the organic extracts were dried, evaporated and purified by preparative reverse phase HPLC (C)₁₈): purifying with gradient/hydrochloric acid modifier (15min) of 1-99% acetonitrile in water to obtain 4- [3- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] amino acid]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-3-methyl-2-pyridinyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (290mg, 61%). ESI-MS M/z calculated 783.27924, Experimental 784.31(M +1)⁺(ii) a Retention time: 2.42min (LC method B).

And 7: 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-3-yl) propylamino ] -5-methyl-2-pyridinyl ] sulfonyl ] -6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide (hydrochloride salt):

a solution of 4- [3- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -3-methyl-2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (290mg, 0.3698mmol) in dichloromethane (6mL) was treated with hydrochloric acid (4M in dioxane) (3mL, 4M, 12.00mmol) and stirred at room temperature for 30min, the mixture was evaporated to dryness under reduced pressure to give 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-3-yl) propylamino ] -5-methyl-2-pyridinyl ] sulfonyl ] -6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide (hydrochloride) (265 mg, 99%). The product was used in the next step without further purification.

And 8: 12, 12, 20-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione:

in a 5mL microwave vial, 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-3-yl) propylamino ] was placed]-5-methyl-2-pyridinyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (hydrochloride) (265mg), potassium carbonate (260mg, 1.881mmol), cesium fluoride (87mg, 0.5727mmol) and

the mixture of MS (300mg) was evacuated/backfilled with nitrogen (3 times). Dimethylsulfoxide (6mL) was added and the mixture stirred at 140 ℃ for 16 h. The reaction mixture was filtered and passed through preparative reverse phase HPLC (C)₁₈): gradient of 1-99% acetonitrile in water/hydrochloric acid modifier (15min) purification to give 12, 12, 20-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl acetate]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (100mg, 42%). ESI-MS M/z calculated 647.2502, Experimental 648.31(M +1) ⁺

And step 9: 12, 12, 20-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 114) and 12, 12, 20-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5(10), 6, 8, 19, 21-hexaene-2, 2, 4-trione (enantiomer 2) (compound 115)

Chromatography by SFC using ChiralPak AS-H (250X 10mM, 5 μm particle size) and 18% methanol (20mM NH)₃) Per 82% carbon dioxide mobile phase (10mL/min over 8.0min) (70. mu.L of 24 mg/mL solution in methanol/dimethylsulfoxide (90: 10) injection volume) to racemic 12, 12, 20-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]The tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (100 mg, 0.07052mmol) was subjected to chiral separation to give 12, 12, 20-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] ketone as the first enantiomer to be eluted ]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 114) (25.8mg, 10%);¹h NMR (400MHz, chloroform-d) 8.19(d, J ═ 2.8Hz, 1H), 8.08(d, J ═ 8.4Hz, 1H), 7.51(d, J ═ 7.3Hz, 1H), 7.42 (d, J ═ 7.3Hz, 1H), 7.24-7.27(m, 1H), 5.90(d, J ═ 2.8Hz, 1H), 4.56(s, 1H), 4.39(t, J ═ 7.2Hz, 2H), 3.93(s, 1H), 3.44-3.32(m, 1H), 3.23(d, J ═ 19.8Hz, 1H), 3.06(t, J ═ 9.3Hz, 1H), 2.72-2.53(m, 1H), 2.14(s, 2.3H), 2.81 (t, 2.0, 0.7H), 0.7H, 0 (ddh), 0.9.9.3H, 0 (H), 0.7.9, 0 (H, 0, 7H, 7H, and one (d, 7.7H; ESI-MS M/z calculated 647.2502, Experimental 648.34 (M +1)⁺(ii) a Retention time: 2.25min. (LC method A) and 12, 12, 20-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as the second enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (p-xylene)Enantiomer 2) (compound 115) (24.7mg, 25%);¹h NMR (400MHz, chloroform-d) 8.19(d, J ═ 2.8Hz, 1H), 8.09(d, J ═ 8.4Hz, 1H), 7.52(d, J ═ 7.3Hz, 1H), 7.43 (d, J ═ 7.4Hz, 1H), 7.28(s, 1H), 5.91(d, J ═ 2.8Hz, 1H), 4.58(d, J ═ 8.1Hz, 1H), 4.39(t, J ═ 7.2Hz, 2H), 3.97(d, J ═ 5.8Hz, 1H), 3.43-3.31(m, 1H), 3.28-3.15(m, 1H), 3.06(t, J ═ 9.8Hz, 1H), 2.65(d, J ═ 6, 1H), 3.0 (t, 2.0, 2H), 2H, 0, and one residual group (d, C; ESI-MS M/z calculated 647.2502, Experimental 648.31(M +1)⁺(ii) a Retention time: 0.85min (LC method A).

Example 29: preparation of 8- [3- ({ dispiro [2.0.2.1 ]]Hept-7-yl } methoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 21-pentaazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 120) and 8- [3- ({ dispiro [2.0.2.1 ] ]Hept-7-yl } methoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 21-pentaazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 121)

Step 1: 2, 2-dimethyl-4- [4- [ (5-sulfamoyl-2-pyridyl) amino ] butyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

A100 mL round bottom flask was charged with 4- (4-aminobutyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.33g, 4.918mmol), 6-chloropyridine-3-sulfonamide (945mg, 4.906mmol), anhydrous dimethyl sulfoxide (15mL), and potassium carbonate (695mg, 5.0 mmol) under nitrogen29mmol) (freshly ground in a mortar) and the mixture stirred at 100 ℃ for 20h after cooling, the reaction was diluted with ethyl acetate (50mL) and poured into a saturated aqueous solution of ammonium chloride (50mL), the phases were separated, the aqueous phase was extracted with ethyl acetate (20mL) and the combined extracts were washed with brine (40 mL), dried over sodium sulfate and evaporated, the residue was purified by flash chromatography on silica gel (80g column) using a gradient of ethyl acetate/hexane (0 to 100% over 30 min.) the solvent was evaporated to give 2, 2-dimethyl-4- [4- [ (5-sulfamoyl-2-pyridyl) amino acid as an off-white solid foam ]Butyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (1.165g, 56%). ESI-MS M/z calculated 426.23007, Experimental value 427.3 (M +1)⁺(ii) a Retention time: 1.4min (LC method B).

Step 2: 4- [4- [ [5- [ [ 2-chloro-6- [3- (dispiro [2.0.2.1] hept-7-ylmethoxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] butyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

A100 mL flask was charged with 2-chloro-6- [3- (dispiro [2.0.2.1] under nitrogen]Hept-7-ylmethoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (355mg, 1.027mmol) and anhydrous tetrahydrofuran (5 mL). Add carbonyldiimidazole (183mg, 1.129mmol) and stir the mixture at room temperature under nitrogen for 3.5h in a separate 20mL vial maintained under nitrogen to prepare 2, 2-dimethyl-4- [4- [ (5-sulfamoyl-2-pyridyl) amino]Butyl radical]A solution of pyrrolidine-1-carboxylic acid tert-butyl ester (438mg, 1.027mmol) in anhydrous tetrahydrofuran (2.5mL) was added to the activated ester solution by syringe. Addition of 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene (0.35 mL, 2.340mmol) and the mixture stirred at room temperature for 19 h. The solvent was evaporated and the residue treated with water (50mL), ethyl acetate (50mL) and hydrochloric acid (1mL, 6M, 6.000 mmol). The two phases were separated, the aqueous phase was further extracted with ethyl acetate (25mL), the combined organics were washed with brine (30mL), dried over sodium sulfate and the solvent was evaporated, the product was dissolved in dichloromethane and flash chromatographed on silica gel (40g gold column) using ethyl acetate The gradient of ester/hexane (0 to 100% over 30min) was purified. The pure product fractions were collected and the solvent was evaporated to give 4- [4- [ [5- [ [ 2-chloro-6- [3- (dispiro [2.0.2.1 ]) as a white solid]Hept-7-ylmethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Butyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (467mg, 60%). ESI-MS M/z calculated 753.30756, Experimental 754.3(M +1)⁺(ii) a Retention time: 2.34min (LC method B).

And step 3: 2-chloro-N- [ [6- [4- (5, 5-dimethylpyrrolidin-3-yl) butylamino ] -3-pyridinyl ] sulfonyl ] -6- [3- (dispiro [2.0.2.1] hept-7-ylmethoxy) pyrazol-1-yl ] pyridine-3-carboxamide (dihydrochloride).

A100 mL round bottom flask was charged with 4- [4- [ [5- [ [ 2-chloro-6- [3- (dispiro [2.0.2.1]]Hept-7-ylmethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Butyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (467mg, 0.6191mmol), dichloromethane (6mL) and hydrochloric acid (0.63mL, 4M, 2.520 mmol) (4M in dioxane.) the reaction was stirred at room temperature for 3h, an additional amount of hydrochloric acid (0.5mL, 4M, 2.000mmol) was added and the mixture was stirred for an additional hour. This procedure was repeated until a white solid was obtained vacuum drying to give 2-chloro-N- [ [6- [4- (5, 5-dimethylpyrrolidin-3-yl) butylamino ] as a white solid ]-3-pyridyl]Sulfonyl radical]-6- [3- (dispiro [2.0.2.1 ]]Hept-7-ylmethoxy) pyrazol-1-yl]Pyridine-3-carboxamide (dihydrochloride) (420mg, 93%). The product was used in the next step without any further purification. ESI-MS M/z calculated 653.2551, Experimental 654.3(M +1)⁺(ii) a Retention time: 1.58min (LC method B).

And 4, step 4: 8- [3- ({ dispiro [2.0.2.1 ]]Hept-7-yl } methoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 21-pentaazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2,2, 4-Tri-one (enantiomer 1) (Compound 120) and 8- [3- ({ Dispiro [2.0.2.1 ]]Hept-7-yl } methoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 21-pentaazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 121)

A100 mL round bottom flask equipped with a magnetic stir bar was charged under nitrogen with 2-chloro-N- [ [6- [4- (5, 5-dimethylpyrrolidin-3-yl) butylamino]-3-pyridyl]Sulfonyl radical]-6- [3- (dispiro [2.0.2.1 ]]Hept-7-ylmethoxy) pyrazol-1-yl]Pyridine-3-carboxamide (dihydrochloride) (420mg, 0.5776mmol), anhydrous NMP (5 mL), potassium carbonate (343mg, 2.482mmol) (freshly ground in a mortar) and caesium fluoride (89mg, 0.5859 mmol.) the mixture is stirred vigorously under nitrogen at 145 ℃ for 13h in a dry bath, followed by 165 ℃ for 8 h. After cooling to room temperature, the mixture was diluted with water (30mL) and acidified (final pH 4-5) by slow addition of hydrochloric acid (600 μ L, 6M, 3.600mmol), the resulting solid was filtered and approximately air dried the solid was dissolved in dichloromethane/ethyl acetate (total volume 50mL), dried over sodium sulfate, filtered and concentrated to give a solution which was purified by silica gel flash chromatography (gold 24g column) using a gradient of methanol/dichloromethane (0 to 5% over 30 min). Solvent was evaporated, triturated in dichloromethane/hexane and solvent evaporated again to give the racemic product AS a white solid (79mg, 22%). chiral SFC chromatography was performed on this racemic material (ChiralPak AS-H (250 × 10mm), 5 μ M column; mobile phase 38% acetonitrile/methanol (90: 10, no modifier), 62% carbon dioxide, 10 mL/min; concentration 24mg/mL in acetonitrile/methanol/dimethyl sulfoxide (80: 10; no modifier) injected at a volume of 70 μ L, 100 bar). The first enantiomer to be eluted was 8- [3- ({ dispiro [2.0.2.1 ]) as a white solid ]Hept-7-yl } methoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 21-pentaazatetracyclo [18.2.2.111, 14.05, 10]Twenty five carbons-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 120) (25mg, 14%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.13 (width s, 1H, from D)₂O substitution), 8.50(br s, 1H), 8.17(d, J ═ 2.7Hz, 1H), 7.88-7.70(M, 2H), 7.34(br s, 1H alternative), 6.90(d, J ═ 8.3Hz, 1H), 6.57(d, J ═ 9.1Hz, 1H), 6.10 (d, J ═ 2.8Hz, 1H), 4.23(d, J ═ 7.0Hz, 2H), 2.54(s, 4H), 2.08(br s, 2H), 1.91(t, J ═ 7.0Hz, 1H), 1.73(d, J ═ 10.4Hz, 1H), 1.57-1.53(M, 9H), 1.34-1.15(M, 1H), 1.05 (br s, 2H), 2.95 (br s, 0.83, J ═ 0, 3H), 0.84 (M, M ═ 3H, 2H), 2H, 5(M, M ═ 3, 2H, 5H), 2H, 5 (esim, 0, 3H), 2H, 0, 3H, 0, 3H, 3, 2H⁺(ii) a Retention time: 2.15min (LC method B) the second enantiomer to be eluted was 8- [3- ({ dispiro [2.0.2.1 ]) as a white solid]Hept-7-yl } methoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 21-pentaazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 121) (24mg, 13%). ¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.11(s, 1H), 8.51 (width s, 1H), 8.17(d, J ═ 2.8Hz, 1H), 7.80(d, J ═ 8.3Hz, overlapping width s, 2H), 7.33(br s, 1H), 6.90(d, J ═ 8.3Hz, 1H), 6.57(d, J ═ 8.9Hz, 1H), 6.10(d, J ═ 2.7Hz, 1H), 4.23(d, J ═ 7.0Hz, 2H), 2.62-2.49 (M, overlapping with solvent signals, possibly 4H), 2.08(br s, 2H), 1.91(t, J ═ 7.0Hz, 1H), 1.72 (br s, 1H), 1.54(M, 9H), 1.24(br s, 1H), 1.92 (br s, 1H), 1.83 (H, 0, 19H), 2H, 19 (M), 2H, 19 (M, M.⁺(ii) a Retention time: 2.15min (LC method B).

Example 30: preparation of 8- [3- ({ dispiro [2.0.2.1 ]]Hept-7-yl } methoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracosane-1 (23), 5(10), 6, 8, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 124) and 8- [3- ({ dispiro [2.0.2.1 ]]Hept-7-yl } methoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracosane-1 (23), 5(10), 6, 8, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 125)

Step 1: 2, 2-dimethyl-5- [3- [ (6-sulfamoyl-2-pyridyl) amino ] propyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 5- (3-aminopropyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (500mg, 1.950mmol) in N, N-dimethylformamide (5mL) was added 6-fluoropyridine-2-sulfonamide (343, 1.950mmol) followed by potassium carbonate (808mg, 5.850 mmol). The flask was capped with a septum and heated in an oil bath at 70 ℃ for 18h under a nitrogen balloon. The organics were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography (80 g column) using a gradient of 100% hexane to 100% ethyl acetate to give 2, 2-dimethyl-5- [3- [ (6-sulfamoyl-2-pyridyl) amino as a white foamy solid]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (428mg, 53%).¹H NMR (400MHz, chloroform-d) 7.51(t, J ═ 7.9Hz, 1H), 7.19(d, J ═ 7.3Hz, 1H), 6.55(d, J ═ 8.5Hz, 1H), 5.51(s, 1H), 5.05(s, 2H), 3.90(s, 1H), 3.57-3.42 (m, 1H), 3.32(d, J ═ 9.8Hz, 2H), 1.91(s, 2H), 1.77(d, J ═ 30.5Hz, 1H), 1.62(d, J ═ 2.9Hz, 3H), 1.48(s, 10H), 1.27(t, J ═ 3.6Hz, 3H). ESI-MS M/z calculated 412.21442, Experimental 413.25(M +1) ⁺(ii) a Retention time: 0.65min (LC method B).

Step 2: 5- [3- [ [6- [ [ 2-chloro-6- [3- (dispiro [2.0.2.1] hept-7-ylmethoxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

A100 mL flask was charged with 2-chloro-6- [3- (dispiro [2.0.2.1] under nitrogen]Hept-7-ylmethoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (327mg, 0.9457mmol) and anhydrous tetrahydrofuran (5mL) carbonyl diimidazole (168mg, 1.036mmol) was added and the mixture was stirred at room temperature under nitrogen for 2h (complete activation was observed by LCMS of sec-butylamine containing aliquots). Preparation of 2, 2-dimethyl-5- [3- [ (6-sulfamoyl-2-pyridyl) amino group in a separate 20mL vial maintained under a nitrogen atmosphere]Propyl radical]A solution of pyrrolidine-1-carboxylic acid tert-butyl ester (390mg, 0.9453mmol) in anhydrous tetrahydrofuran (2.5mL) and added to the activated ester solution by syringe 1, 8-diazabicyclo [5.4.0 ] was added]Undec-7-ene (0.32mL, 2.140mmol) and the mixture stirred at room temperature for 13 h. The solvent was evaporated and the residue treated with water (50mL), ethyl acetate (50mL) and hydrochloric acid (1mL, 6M, 6.000 mmol). The two phases were separated. The aqueous phase was further extracted with ethyl acetate (25 mL). The combined organics were washed with brine (30mL), dried over sodium sulfate and the solvent was evaporated. The product was dissolved in dichloromethane and purified by flash chromatography on silica gel (40g gold column) using a gradient of ethyl acetate/hexane (0 to 100% over 30 min.) the pure fractions were collected and the solvent was evaporated to give 5- [3- [ [6- [ [ 2-chloro-6- [3- (dispiro [2.0.2.1] as a white solid ]Hept-7-ylmethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (435mg, 62%). ESI-MS M/z calculated 739.2919, Experimental 740.3(M +1)⁺(ii) a Retention time: 2.47min (LC method B).

And step 3: 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-2-yl) propylamino ] -2-pyridinyl ] sulfonyl ] -6- [3- (dispiro [2.0.2.1] hept-7-ylmethoxy) pyrazol-1-yl ] pyridine-3-carboxamide (dihydrochloride).

A100 mL round bottom flask was charged with 5- [3- [ [6- [ [ 2-chloro-6- [3- (dispiro [2.0.2.1]]Hept-7-ylmethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (435mg, 0.5876mmol), dichloromethane (6mL) and hydrochloric acid (0.6mL, 4M, 2.400mmol) (4M in dioxane.) the reaction was stirred at room temperature for 3h, an additional amount of hydrochloric acid (500 μ L, 4M, 2.000 mmol) was added and the mixture was stirred for an additional hour. The volatiles were removed by vacuum evaporation the residue was triturated with dichloromethane/hexane and the solvent evaporated the operation was repeated until a white solid was obtained. Drying under vacuum to obtain 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-2-yl) propylamino ] as white solid ]-2-pyridyl]Sulfonyl radical]-6- [3- (dispiro [2.0.2.1 ]]Hept-7-ylmethoxy) pyrazol-1-yl]Pyridine-3-carboxamide (dihydrochloride) (439 mg, 105%). this product was used in the next step without any further purification ESI-MS calcd for M/z 639.23944, experimental 640.3(M +1)⁺(ii) a Retention time: 1.7min (LC method B).

And 4, step 4: 8- [3- ({ dispiro [2.0.2.1 ]]Hept-7-yl } methoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracosane-1 (23), 5(10), 6, 8, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 124) and 8- [3- ({ dispiro [2.0.2.1 ]]Hept-7-yl } methoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracosane-1 (23), 5(10), 6, 8, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 125)

A100 mL round bottom flask equipped with a magnetic stir bar was charged under nitrogen with 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-2-yl) propylamino]-2-pyridyl]Sulfonyl radical]-6- [3- (dispiro [2.0.2.1 ]]Hept-7-ylmethoxy) pyrazol-1-yl]Pyridine-3-carboxamide (dihydrochloride) (4) 39mg, 0.6156mmol), anhydrous NMP (5 mL), potassium carbonate (410mg, 2.967mmol) (freshly ground in a mortar) and cesium fluoride (94.82mg, 23.04 μ L, 0.6242mmol). the mixture was stirred vigorously under nitrogen at 145 ℃ in a dry bath for 46h, then stirred at 155 ℃ for 14h, after cooling to room temperature, the mixture was diluted with water (30mL) and acidified (final pH 4-5) by slow addition of hydrochloric acid (500 μ L, 6M, 3.000 mmol). The solid was dissolved in dichloromethane (total volume 50mL), dried over sodium sulfate, filtered and concentrated, followed by flash chromatography on silica gel (4g column) using a gradient of methanol/dichloromethane (0 to 5% over 30 min). Evaporation of the solvent, trituration in dichloromethane/hexane and evaporation of the solvent again gave the expected racemic product as an off-white solid (154mg, 41%). chiral SFC chromatography was performed on the racemic material (ChiralPak IG column (250 × 21.2mm), 5 μm, mobile phase 38% acetonitrile: methanol (90: 10, no modifier), 62% carbon dioxide, 70mL/min, 30mg/mL in acetonitrile: methanol (90: 10, no modifier) injected at a volume of 500 μ L, 100 bar.) after evaporation of the solvent, the residue was triturated in dichloromethane/hexane and the solvent was removed. The first enantiomer to be eluted was 8- [3- ({ dispiro [2.0.2.1 ]) isolated as a white solid ]Hept-7-yl } methoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracosane-1 (23), 5(10), 6, 8, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 124) (62 mg, 33%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.70 (width s, 1H), 8.21(d, J ═ 2.8Hz, 1H), 8.00 (width d, J ═ 8.0Hz, 1H), 7.58(dd, J ═ 8.5, 7.2Hz, 1H), 7.28(br s, 1H), 7.08 (br s, 1H), 7.03(d, J ═ 7.2Hz, 1H), 6.62(d, J ═ 8.4Hz, 1H), 6.12(d, J ═ 2.8Hz, 1H), 4.24(d, J ═ 7.0Hz, 2H), 3.71(br s, 2H), 3.11(br s, 1H), 2.00-1.80(M, 3), 1.73(br s, 2H), 1.63-1.43(M, 5H), 1.11 (br s, 1H), 2.00-1.80(M, 3), 1.73(br s, 2H), 1.63-1.42H), 1.42-0.42 (M), 0.42-0.5H), 0.5 (M, 0.31, 0.5 (M, 1H), 0.5 (M, 1M, 3, 0.5 (M, 0.5M, 1H), and the calculated values (M, 1H).⁺(ii) a Retention time: 1.95min (LC method B.) the second enantiomer to be eluted is white8- [3- ({ dispiro [2.0.2.1 ]) separated as a colored solid]Hept-7-yl } methoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ] ]Tetracosane-1 (23), 5(10), 6, 8, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 125) (54mg, 28%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.67 (width s, 1H), 8.21(d, J ═ 2.8Hz, 1H), 8.00(br d, J ═ 7.1Hz, 1H), 7.58(t, J ═ 7.8Hz, 1H), 7.37-7.21(M, 1H), 7.08(br s, 1H), 7.03(d, J ═ 7.1Hz, 1H), 6.62(d, J ═ 8.5Hz, 1H), 6.12(d, J ═ 2.8Hz, 1H), 4.24 (d, J ═ 7.1Hz, 2H), 3.71(br s, 2H), 3.10(br s, 1H), 2.02-1.79(M, 3H), 1.73(s, 2H), 1.64-1.45(M, 5H), 1.42 (br s, 1H), 0.77(M, 0.25H), 0.54(M, 0.5H), 0.5 (M, 0.5H), 0.25 (M, 0.5M, 0, 1H), calculated values (M, 1H), 4.12 (d, 1H), 4, 1H.⁺(ii) a Retention time: 1.96min (LC method B).

Example 31: preparation of (14S) -8- [3- (3, 3-dimethylbutyl) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (diastereomer 1) (compound 126) and (14S) -8- [3- (3, 3-dimethylbutyl) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (diastereomer 2) (compound 127)

Step 1: (14S) -8- [3- (3, 3-dimethylbutyl) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (diastereomer 1) (compound 126) and (14S) -8- [3- (3, 3-dimethylbutyl) -2-oxopyrrolidin-1-yl]-12，12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (diastereomer 2) (compound 127)

P- (14S) -8- [3- (3, 3-dimethylbutyl) -2-oxopyrrolidin-1-yl group]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione were subjected to chiral SFC separation (ChiralCel OJ-H (250X 10mm), 5. mu.M column; mobile phase 25% acetonitrile/methanol (90: 10, no modifier), 75% carbon dioxide, 10 mL/min; concentration 24mg/mL in acetonitrile/methanol (90: 10); injection volume 70. mu.L, 100 bar).

For the collected pure fractions, the solvent was evaporated and the residue was triturated in dichloromethane/hexane. The first diastereomer to elute is (14S) -8- [3- (3, 3-dimethylbutyl) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (diastereomer 1) (compound 126) (19mg, 36%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.42(s, 1H), 7.68(d, J ═ 8.4Hz, 1H), 7.62 to 7.46(m, 2H), 7.03(d, J ═ 7.0Hz, 1H), 6.97 (width s, 1H), 6.70(d, J ═ 8.6Hz, 1H), 4.04 (t, J ═ 9.3Hz, 1H), 3.99 to 3.83(m, 1H), 3.74(q, J ═ 10.3, 9.7Hz, 1H), 3.10(br s, 1H), 2.94(d, J ═ 13.5Hz, 1H), 2.76 to 2.63(m, 1H), 2.24(dd, J ═ 17.4, 7.7Hz, 1H), 2.10 (br s, 1H), 1.88 to 1.88 (m, 1H), 1.64(m, 1H), 9.40H, 1H), 1H, and 1H. ESI-MS M/z calculated 582.2988, Experimental 583.4(M +1)⁺(ii) a Retention time: 2.13min (LC method B.) the second diastereomer to be eluted is (14S) -8- [3- (3, 3-dimethylbutyl) -2-oxopyrrolidin-1-yl ]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18,23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (diastereomer 2) (compound 127) (17mg, 32%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.42(s, 1H), 7.68(d, J ═ 8.5Hz, 1H), 7.61-7.49(m, 2H), 7.04(d, J ═ 7.1Hz, 1H), 6.97 (width d, J ═ 7.0Hz, 1H), 6.70(d, J ═ 8.4Hz, 1H), 3.96-3.79(m, 3H), 3.09(br, 1H), 2.93(br d, J ═ 13.3Hz, 1H), 2.75-2.55 (m, 2H), 2.30-2.18(m, 1H), 2.09(br, 1H), 1.88-1.69(m, 3H), 1.69-1.41(m, 10H), 1.34-1.15(m, 4H), 0.88(s, 9H). ESI-MS M/z calculated 582.2988, Experimental 583.4 (M +1)⁺(ii) a Retention time: 2.14min (LC method B).

Example 32: preparation of 12, 12, 22-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 129)

Step 1: 2-benzylsulfanyl-6-chloro-3-methyl-pyridine

2, 6-dichloro-3-methyl-pyridine (5.05g, 31.17mmol) and phenylmethanethiol (3.871g, 3.659 mL, 31.17mmol) were dissolved in tetrahydrofuran (50.50mL) and sodium tert-butoxide (31.17mL, 2M, 62.34mmol) was added. The reaction was stirred for 16h and partitioned between water and ethyl acetate the organics were separated, washed with brine, dried over sodium sulfate, filtered and evaporated. The crude material, 2-benzylsulfanyl-6-chloro-3-methyl-pyridine (7.15g, 92%) was used without further purification ESI-MS M/z calculated 249.0379, experimental 250.0(M +1) ⁺(ii) a Retention time: 0.81min (LC method A).

Step 2: 6-chloro-3-methyl-pyridine-2-sulfonamide

A biphasic mixture of 2-benzylsulfanyl-6-chloro-3-methyl-pyridine (7.15g, 28.63mmol) in dichloromethane (42.90mL), water (14.30mL), and hydrochloric acid (2.863mL, 1M, 2.863mmol) was cooled in a brine ice bath (hydrochloric acid was added to avoid otherwise adding Cl)₂Time delayed exotherm) one hour of Cl₂(8.119 g, 114.5mmol) was bubbled through the solution (3 times at 2min intervals.) after stirring the reaction at 0 deg.C. 1.5h, the reaction was added dropwise to ice bath cooled NH₄OH solution (43.01mL, 28% w/v, 343.6 mmol.) the reaction was allowed to warm to room temperature and stirred for 15 min. The reaction mixture was partitioned between ethyl acetate (60 mL) and water (20mL), the organics were separated and the aqueous layer was extracted with ethyl acetate (2X 60 mL). The organics were combined, washed with brine, dried over sodium sulfate, filtered and evaporated. The resulting solid was triturated with dichloromethane (30mL) and filtered. The solid was washed with a minimum amount of dichloromethane to give an off-white solid, 6-chloro-3-methyl-pyridine-2-sulfonamide (2.95g, 50%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)7.94(d, J ═ 8.1, 0.9Hz, 1H), 7.68(d, J ═ 8.1Hz, 1H), 7.63(s, 2H), 2.55(s, 3H). ESI-MS M/z calculated 205.99167, Experimental 207.1(M +1) ⁺(ii) a Retention time: 0.3min (LC method A).

And step 3: 2, 2-dimethyl-4- [3- [ (5-methyl-6-sulfamoyl-2-pyridyl) amino ] propyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

To a nitrogen purged microwave reaction vial was added 6-chloro-3-methyl-pyridine-2-sulfonamide (1.12g, 5.420 mmol), 4- (3-aminopropyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1g, 3.900mmol), diisopropylethylamine (2.520g, 3.396mL, 19.50mmol), and n-butanol (11 mL). Sealing the small bottleSealed and stirred at 125 ℃ for 20 h. The solvent was removed in vacuo and the residue was dissolved in dichloromethane and washed with water the organic extracts were dried over sodium sulfate, evaporated and purified by silica gel chromatography (gradient of 0 to 85% ethyl acetate/hexane) to give 2, 2-dimethyl-4- [3- [ (5-methyl-6-sulfamoyl-2-pyridyl) amino]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (360mg, 22%). ESI-MS M/z calculated 426.23007, Experimental 427.29 (M +1)⁺(ii) a Retention time: 0.67min (LC method A).

And 4, step 4: 4- [3- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -5-methyl-2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (317.1 mg, 0.8439mmol) and carbonyldiimidazole (136.8mg, 0.8439mmol) were combined in dry tetrahydrofuran (8.5mL) and stirred at 50 ℃ for 90 min. Followed by addition of 2, 2-dimethyl-4- [3- [ (5-methyl-6-sulfamoyl-2-pyridyl) amino]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (360mg, 0.8439mmol) was added followed by 1, 8-diazabicyclo [5.4.0]Undec-7-ene (128.5mg, 126.2 μ L, 0.8439mmol) and the reaction was heated at 50 ℃ for 15h. The organics were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel using a gradient of 100% hexane to 75% ethyl acetate/hexane to give 4- [3- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] as an off-white solid]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-5-methyl-2-pyridinyl]Amino group]Propyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (326mg, 49%). ESI-MS M/z calculated 783.27924, Experimental 784.42(M +1)⁺(ii) a Retention time: 0.89min (LC method A).

And 5: 12, 12, 22-trimethyl-8- (3- {2- [1- (trifluoromethyl) methyl) Cyclopropyl group]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 129)

Part A: tert-butyl 4- [3- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -5-methyl-2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylate (186mg, 0.2372mmol) was dissolved in dichloromethane (3mL) and hydrochloric acid (4M in dioxane) (2.2mL, 4M, 8.800mmol) was added to the mixture and the mixture was stirred at room temperature for 30 min. The mixture was concentrated to dryness under reduced pressure and directly taken to the next step.

And part B: the material from part A was combined with potassium carbonate (197mg, 1.425mmol), cesium fluoride (60 mg, 0.3950mmol),

Molecular sieves and dimethylsulfoxide (3mL) were combined in a vial, purged with nitrogen, capped, heated to 140 ℃ and stirred for 16 h. The reaction mixture was cooled to room temperature, filtered and then chromatographed by reverse-phase preparative HPLC using C₁₈Column and 30-99A1-B1 gradient (acetonitrile-water +5mM hydrochloric acid 30min, X2 injections) to give 12, 12, 22-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid ]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 129) (53mg, 34%). ESI-MS M/z calculated 647.2502, Experimental 648.31(M +1)⁺(ii) a Retention time: 2.29min (LC method B).

Example 33: preparation of 8- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 21-pentaazatetracyclo [18.2.2.111, 14.05, 10]Twenty-five carbons-1 (22),5, 7, 9, 20, 23-hexaen-2, 2, 4-trione (Compound 130)

Step 1: 4- [4- [ [5- [ [ 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] butyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (356.3mg, 0.9846mmol) and carbonyldiimidazole (159.7mg, 0.9846mmol) were combined in tetrahydrofuran (5mL) and stirred at room temperature for 16h, then 2, 2-dimethyl-4- [4- [ (5-sulfamoyl-2-pyridyl) amino ] was added]Butyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (350mg, 0.8205mmol) and 1, 8-diazabicyclo [5.4.0 ]Undec-7-ene (187.4 mg, 184.1 μ L, 1.231mmol) and the reaction stirred at room temperature for 6 h. The reaction was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution, followed by brine. The organic layer was separated, dried over sodium sulfate, filtered and evaporated, followed by chromatography on silica gel using a gradient of 100% dichloromethane to 20% methanol/dichloromethane to give 4- [4- [ [5- [ [ 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl ] as a white solid]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Butyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (423mg, 67%).¹H NMR (400MHz, chloroform-d) 8.70(s, 1H), 8.27(d, J ═ 2.9Hz, 1H), 8.19(d, J ═ 8.5Hz, 1H), 8.08(d, J ═ 8.9Hz, 1H), 7.70(d, J ═ 8.5Hz, 1H), 6.41 (d, J ═ 8.9Hz, 1H), 5.95(d, J ═ 2.9Hz, 1H), 5.48(brs, 1H), 4.41(t, J ═ 6.8Hz, 2H), 3.64(dt, J ═ 40.0, 9.2Hz, 1H), 3.34(s, 2H), 2.85(q, J ═ 11.1Hz, 1H), 2.06(d, J ═ 14.5, 1H), 6.6H, 1H, 4.86 (t, 6H), 6.6H, 1H, 6H, 4.6H, 6H, 1H, 6H, 4.6H, 1H, 6H, 1H, 6H, 1H, 6H, 1H, 4H5.8Hz, 7H), 1.27(d, J ═ 18.6Hz, 3H), 0.65(tq, J ═ 8.3, 5.0, 4.1Hz, 2H), 0.51-0.36(m, 4H), 0.35-0.26(m, 1H), 0.24-0.14(m, 2H), 0.13-0.04 (m, 2H). ESI-MS M/z calculated 769.3388, Experimental 770.45(M +1) ⁺(ii) a Retention time: 0.91min (LC method A).

Step 2: 8- [3- (3, 3-Dicyclopropylpropoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 21-pentaazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (22), 5, 7, 9, 20, 23-hexaen-2, 2, 4-trione (compound 130)

4- [4- [ [5- [ [ 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl ] is reacted at room temperature]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Butyl radical]A solution of tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (415mg, 0.5387 mmol) in dichloromethane (2mL) and trifluoroacetic acid (614.2mg, 412.2 μ L, 5.387mmol) was stirred for 4h then the solvent was evaporated. The residue was dissolved in ethyl acetate, washed with 2mL of a saturated solution of sodium bicarbonate and the solvent was evaporated to give a residue, which was dissolved in dimethylsulfoxide (5 mL). Adding

Molecular sieves and stir the mixture for 10 min. Cesium fluoride (245.5mg, 1.616mmol) and potassium carbonate (223.3mg, 1.616mmol) were then added and the reaction mixture was heated at 160 ℃ for 24H, filtered through Whatman filter disc (puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS method using a double gradient run of 50-90% mobile phase B over 15.0 min (mobile phase a ═ water (0.05% hydrochloric acid), mobile phase B ═ acetonitrile) to give 8- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl as a white solid ]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 21-pentaazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (22), 5, 7, 9, 20, 23-hexaen-2, 2, 4-trione (compound 130) (52mg, 15%).¹H NMR (400MHz, chloroform)-d)8.65(s, 1H), 8.18(d, J ═ 2.8Hz, 1H), 7.76(d, J ═ 8.4Hz, 1H), 7.01(d, J ═ 8.3Hz, 1H), 6.52(d, J ═ 9.1Hz, 1H), 5.89(d, J ═ 2.8Hz, 1H), 5.24(s, 1H), 4.41(t, J ═ 6.8Hz, 2H), 3.36(s, 1H), 2.69(s, 1H), 2.23(s, 1H), 2.06(brs, 1H), 1.97(q, J ═ 6.8Hz, 2H), 1.78-1.71(m, 3H), 1.66(brs, 1H), 1.63(brs, 1H), 1.60 (q, 6.8Hz, 2H), 1.78-1.71(m, 3H), 1.66(brs, 1H), 1.63(brs, 1H), 0.60 (g, 3H), 0.9, 0.8H, 2H), 3H, 2H, 3H, 0.9H, 0 (dd0 (1H), 3H, 9H), 0.9H, 2H, 0 (1H), 2H) 0.11(M, 2H). ESI-MS M/z calculated 633.30975, Experimental 634.22(M +1)⁺(ii) a Retention time: 1.66min (LC method B).

Example 34: preparation of 8- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracosane-1 (23), 5(10), 6, 8, 20(24), 21-hexaen-2, 2, 4-trione (compound 131)

Step 1: 5- [3- [ [6- [ [ 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (300mg, 0.8291 mmol) and bis (imidazol-1-yl) methanone (117.9mg, 0.7272mmol) were combined in tetrahydrofuran (2.5mL) and stirred at room temperature for 16 h. Subsequently, 2-dimethyl-5- [3- [ (6-sulfamoyl-2-pyridyl) amino group was added]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (250.0mg, 0.6060mmol) and 1, 8-diazabicyclo [5.4.0]Undec-7-ene (138.4mg, 136.0 μ L, 0.9090mmol) and the reaction stirred at room temperature for 4 h. The reaction was diluted with ethyl acetate and washed with ammonium chlorideThe organics were separated, dried over sodium sulfate, filtered and evaporated. The resulting brown residue was purified by silica gel chromatography using a gradient of 100% dichloromethane to 20% methanol/dichloromethane to give 5- [3- [ [6- [ [ 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl ] as a white solid]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical ]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (356mg, 78%). ESI-MS M/z calculated 755.3232, Experimental 756.5(M +1)⁺(ii) a Retention time: 0.63min (LC method A).

Step 2: 8- [3- (3, 3-Dicyclopropylpropoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracosane-1 (23), 5(10), 6, 8, 20(24), 21-hexaen-2, 2, 4-trione (compound 131)

Reacting 5- [3- [ [6- [ [ 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl ] at room temperature]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]A solution of tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (356mg, 0.4707 mmol) in dichloromethane (2mL) and trifluoroacetic acid (536.7mg, 360.2 μ L, 4.707mmol) was stirred for 4h then the solvent was evaporated the residue was dissolved in ethyl acetate, washed with 2mL of saturated aqueous sodium bicarbonate solution and the solvent was evaporated and dried under high vacuum. The resulting residue was dissolved in dimethyl sulfoxide (5mL) and added

Molecular sieves and stir the reaction mixture for 10 min. Subsequently, cesium fluoride (214.5mg, 1.412mmol) and potassium carbonate (195.1mg, 1.412mmol) were added, and the reaction mixture was heated at 150 ℃ overnight. The reaction mixture was filtered through Whatman filter disc (puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS method using a double gradient run of 50-90% mobile phase B over 15.0min (mobile phase a ═ water (0.05% hydrochloric acid), mobile phase B ═ acetonitrile) to give a solid phase as 8- [3- (3, 3-Dicyclopropylpropoxy) -1H-pyrazol-1-yl as white solid]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracosane-1 (23), 5(10), 6, 8, 20(24), 21-hexaen-2, 2, 4-trione (compound 131) (115mg, 39%).¹H NMR (400MHz, chloroform-d) (s, 1H), 8.47(d, J ═ 8.6Hz, 1H), 8.26-8.06(m, 1H), 7.66(d, J ═ 15.1Hz, 1H), 7.51-7.40(m, 2H), 6.45(d, J ═ 7.8Hz, 1H), 5.95(d, J ═ 2.8Hz, 1H), 4.82(s, 1H), 4.43(t, J ═ 6.8Hz, 2H), 4.16(d, J ═ 72.4Hz, 1H), 3.34(s, 1H), 3.09(s, 1H), 2.38(d, J ═ 8.4Hz, 2H), 1.97(q, J ═ 6.8Hz, 2H), 1.65(d, 42 (d, 1H), 2.38(d, J ═ 8.4Hz, 2H), 1.97(q, J ═ 6.8, 8H, 2H), 1.8H, 0.7 (J ═ 0, 0.6.8H, 0, 3.8H), 3.7 (J ═ 0, 3.8H), 3.6.6H, 0, 3.6H, 3, 0.09(dtd, J ═ 9.0, 4.9, 3.4Hz, 2H) ESI-MS M/z calcd 619.29407, experimental 620.17(M +1)⁺(ii) a Retention time: 1.61min (LC method B).

Example 35: preparation of 12, 12, 19-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl-)]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 21-pentaazatetracyclo [18.2.2.111, 14.05, 10 ]Pentacosane-1 (23), 5, 7, 9, 20(24), 21-hexaene-2, 2, 4-trione (compound 132)

Step 1: 2, 2-dimethyl-4- [4- (methylamino) butyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

To a 50mL round bottom flask containing 4- (4-aminobutyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (850mg, 3.143 mmol) in dichloromethane (15mL) was added acetic anhydride (400. mu.L, 4.239mmol) followed by triethylamine (1000. mu.L, 7.175 mmol). The vessel was capped and the reaction mixture was stirred at room temperatureAnd (4) 45 min. The combined organic extracts were washed with saturated aqueous sodium carbonate (2 × about 10mL), dried over sodium sulfate, filtered and concentrated in vacuo to give a clear oil, which was charged to a 100mL round bottom flask and N, N-dimethylformamide (15mL) was added, followed by sodium hydride (200mg, 60% w/w, 5.000 mmol), and the reaction mixture was stirred at room temperature for 30 min. Adding methyl iodide (800 μ L, 12.85mmol), capping the vessel, and stirring the reaction mixture at 50 ℃ for 48h after cooling to room temperature, quenching the reaction with water (about 15mL), extracting the crude mixture with dichloromethane (3 × 25mL), and drying the combined organic extracts over sodium sulfate, filtering, and concentrating in vacuo, purifying the crude reaction mixture by silica gel column chromatography (0% -30% ethyl acetate/hexane gradient) to give a yellow oil, which was charged to a 100mL round bottom flask and added methanol (30 mL) and potassium hydroxide (1.5g, 26.74mmol), the flask was equipped with a reflux condenser and after stirring the reaction mixture at 80 ℃ for 96h to cool to room temperature, removing the solvent in vacuo and dissolving the residue in ethyl acetate (about 70mL) and water (about 30mL), separating the layers, and extracting the aqueous layer with ethyl acetate (3 × 20mL), washing the combined organic extracts with water (2 × 25mL), dried over sodium sulfate, filtered and concentrated in vacuo to give crude 2, 2-dimethyl-4- [4- (methylamino) butyl ] as an orange/yellow oil ]Pyrrolidine-1-carboxylic acid tert-butyl ester (873mg, 98%) was used without further purification ESI-MS M/z calculated 284.24637, experimental 285.2(M +1)⁺(ii) a Retention time: 1.19min (LC method B).

Step 2: 2, 2-dimethyl-4- [4- [ methyl- (5-sulfamoyl-2-pyridyl) amino ] butyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

To the solution is charged with 2, 2-dimethyl-4- [4- (methylamino) butyl]A20 mL vial of pyrrolidine-1-carboxylic acid tert-butyl ester (350mg, 1.230 mmol) was charged with 6-chloropyridine-3-sulfonamide (249mg, 1.293mmol) and potassium carbonate (250 mg, 1).809mmol) and dimethyl sulfoxide (4mL) the headspace was purged with nitrogen, the vial was capped, and the reaction mixture was stirred at 120 ℃ for 18 h. After 18h, the reaction was cooled to room temperature and diluted with ethyl acetate (about 40 mL.) the crude mixture was washed with water (10mL) and brine (5mL), and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude reaction mixture was purified by silica gel column chromatography (0% to 100% ethyl acetate/hexane gradient) to give 2, 2-dimethyl-4- [4- [ methyl- (5-sulfamoyl-2-pyridyl) amino group as an off-white solid]Butyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (143mg, 26%). ESI-MS M/z calculated 440.24573, Experimental 441.2(M +1) ⁺(ii) a Retention time: 1.6min (LC method B).

And step 3: 4- [4- [ [5- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] -methyl-amino ] butyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To the solution containing 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl group]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (136 mg, 0.3620mmol) in a 20mL vial was added carbonyldiimidazole (59mg, 0.3639mmol) and tetrahydrofuran (2mL), the vial was capped and the reaction mixture was stirred at room temperature for 2h at which time 2, 2-dimethyl-4- [4- [ methyl- (5-sulfamoyl-2-pyridyl) amino ] was added]Butyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (143 mg, 0.3246mmol) in tetrahydrofuran (2mL) followed by the addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (75 μ L, 0.5015 mmol). The reaction mixture was stirred at room temperature for 18h, then quenched with water (about 4mL) and 1M aqueous citric acid (about 4mL), and the crude mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo the residue was purified by silica gel column chromatography (0% -100% ethyl acetate/hexanes gradient) to give 4- [4- [ [5- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] as an off-white solid ]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]-methyl-amino]Butyl radical]-2, 2-dimethylTert-butyl yl-pyrrolidine-1-carboxylate (167mg, 64%). ESI-MS M/z calculated 797.2949, Experimental 798.4(M +1)⁺(ii) a Retention time: 2.35min (LC method B).

And 4, step 4: 2-chloro-N- [ [6- [4- (5, 5-dimethylpyrrolidin-3-yl) butyl-methyl-amino ] -3-pyridinyl ] sulfonyl ] -6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide (dihydrochloride)

To the reaction vessel is charged with 4- [4- [ [5- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] group]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]-methyl-amino]Butyl radical]20mL Vial of tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (167mg, 0.2092mmol) was added CH₂Cl₂(5mL) and dioxane containing hydrochloric acid (1mL, 4.0M, 4.000 mmol.) the vial was sealed and the reaction mixture was stirred at room temperature for 2h]-3-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (dihydrochloride) (147mg, 91%) was used without further purification. ESI-MS M/z calculated 697.2425, Experimental 698.4(M +1) ⁺(ii) a Retention time: 1.69min (LC method B).

And 5: 12, 12, 19-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 21-pentaazatetracyclo [18.2.2.111, 14.05, 10]Pentacosane-1 (23), 5, 7, 9, 20(24), 21-hexaene-2, 2, 4-trione (compound 132)

To the solution containing 2-chloro-N- [ [6- [4- (5, 5-dimethylpyrrolidin-3-yl) butyl-methyl-amino group]-3-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine compoundA20 mL vial of-3-carboxamide (dihydrochloride) (147mg, 0.2105mmol) was charged with potassium carbonate (152mg, 1.100mmol), CsF (96 mg, 0.6320mmol), and dimethyl sulfoxide (5 mL). The headspace was purged with nitrogen, the vial was capped, and the reaction mixture was stirred at 150 ℃ for 18h after cooling to room temperature, the solid was filtered off with ethyl acetate eluent, the crude mixture was diluted with ethyl acetate (ca. 35mL), washed with 1.0M aqueous citric acid (2 x 5mL), brine (5mL), the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo column chromatography (silica, gradient of 0% to 5% methanol/dichloromethane) to afford 12, 12, 19-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as an off-white solid ]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 21-pentaazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (dihydrochloride) (compound 132) (64mg, 39%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.19(s, 1H), 8.18(d, J ═ 2.8Hz, 1H), 7.81(d, J ═ 8.3Hz, 1H), 6.90(d, J ═ 8.3Hz, 1H), 6.81(s, 1H), 6.10(d, J ═ 2.7Hz, 1H), 4.31(t, J ═ 7.0Hz, 2H), 2.98(d, J ═ 7.8Hz, 3H), 2.37(s, 1H), 2.07(t, J ═ 7.1Hz, 4H), 1.78-1.68(m, 1H), 1.52(s, 8H), 1.39(d, J ═ 51.3Hz, 2H), 1.27-1.05(m, 2H), 1.04-0.75(m, 6H). ESI-MS M/z calculated 661.2658, Experimental 662.4(M +1)⁺(ii) a Retention time: 1.84min (LC method B).

Example 36: preparation of 12, 12, 18-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 133)

Step 1: 2, 2-dimethyl-4- [3- (methylamino) propyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

To a 50mL flask containing tert-butyl 4- (3-aminopropyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (869mg, 3.389 mmol) in dichloromethane (15mL) was added acetic anhydride (527.3mg, 487.3. mu.L, 5.165 mmol) followed by Et3N (884.8mg, 1.219mL, 8.744 mmol). The vessel was capped and the reaction mixture was stirred at room temperature for 45min, then quenched with saturated aqueous sodium carbonate (about 10mL) and extracted with dichloromethane (3 × about 15 mL.) the combined organic extracts were washed with saturated aqueous sodium carbonate (2 × about 10mL), dried over sodium sulfate, filtered and concentrated in vacuo to give the crude acetate, which was combined with N, N-dimethylformamide (15mL), followed by addition of NaH (225mg, 60% w/w, 5.626mmol) and stirring of the reaction mixture at room temperature for 30 min. Methyl iodide (1000 μ L, 16.06mmol) was added, the vessel was capped, and the reaction mixture was stirred at 50 ℃ for 48 h. After cooling to room temperature, the reaction was quenched with water (ca. 15mL) and the crude mixture was extracted with dichloromethane (3 × 25 mL.) the combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo column chromatography (silica gel, 0% to 30% ethyl acetate/hexanes) afforded the methylated intermediate acetate to which methanol (30mL) and KOH (1.5g, 26.74mmol) were added. The flask was equipped with a reflux condenser and the reaction mixture was stirred at 80 ℃ for 96 h. After cooling to room temperature, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate (about 70mL) and water (about 30mL), the layers were separated and the aqueous layer was extracted with ethyl acetate (3X 20 mL). The combined organic extracts were washed with water (2 × 25mL), dried over sodium sulfate, filtered and concentrated in vacuo to give 2, 2-dimethyl-4- [3- (methylamino) propyl ] as an orange/yellow oil ]Pyrrolidine-1-carboxylic acid tert-butyl ester (889mg, 97%) was used without further purification. ESI-MS M/z calculated 270.23074, Experimental 271.2(M +1)⁺(ii) a Retention time: 1.1min (LC method B).

Step 2: 2, 2-dimethyl-4- [3- [ methyl- (6-sulfamoyl-2-pyridyl) amino ] propyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

To 2, 2-dimethyl-4- [3- (methylamino) propyl group]To a solution of pyrrolidine-1-carboxylic acid tert-butyl ester (154mg, 0.5695 mmol) in dimethyl sulfoxide (2mL) was added 6-fluoropyridine-2-sulfonamide (103mg, 0.5847 mmol) followed by diisopropylethylamine (500. mu.L, 2.871 mmol). The flask was capped with a septum and heated in an oil bath under a nitrogen balloon at 90 ℃ for 14 h. The reaction mixture was cooled to room temperature, then diluted with ethyl acetate and washed with brine solution. The organics were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography (80 g column) using a gradient system of 100% hexane to 100% ethyl acetate to give 2, 2-dimethyl-4- [3- [ methyl- (6-sulfamoyl-2-pyridyl) amino as a white solid]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (141mg, 58%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)7.65(dd, J ═ 8.6, 7.2Hz, 1H), 7.12(s, 2H), 7.01(d, J ═ 7.2Hz, 1H), 6.78(d, J ═ 8.7Hz, 1H), 3.53 (q, J ═ 7.8, 7.4Hz, 3H), 3.17(d, J ═ 3.6Hz, 1H), 3.04(s, 3H), 2.84-2.72(m, 1H), 2.09(d, J ═ 9.5Hz, 1H), 1.88(td, J ═ 12.8, 5.7Hz, 1H), 1.53(dt, J ═ 14.6, 7.4Hz, 2H), 1.36(dd, J ═ 15.0, 10.6, 14H), 1.23H (s, 3H). ESI-MS M/z calculated 426.23007, Experimental 427.3(M +1) ⁺(ii) a Retention time: 0.47min (LC method A).

And step 3: 4- [3- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] -methyl-amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

In a 20mL scintillation vial, 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (264mg, 0.7026mmol) and carbonyldiimidazole (114mg, 0.7031mmol) were combined in tetrahydrofuran (2.2mL) and stirred loose at 50 ℃ for 120min2, 2-dimethyl-4- [3- [ methyl- (6-sulfamoyl-2-pyridyl) amino]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (130mg, 0.3048mmol) in tetrahydrofuran (3mL) followed by the addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (92.80 mg, 91.16. mu.L, 0.6096 mmol). The reaction was heated at 50 ℃ for 16 h. The reaction was diluted with ethyl acetate (25mL) and washed with saturated aqueous ammonium chloride solution (25mL), followed by brine (25 mL.) the organic layer was separated, dried over sodium sulfate, filtered and evaporated then the crude material was purified by silica gel chromatography using a gentle gradient of 100% dichloromethane to 20% methanol/dichloromethane the product (still contaminated with 7% SM) was dissolved in ethyl acetate (50mL) and washed with saturated aqueous sodium bicarbonate solution (2 x 50mL), dried over sodium sulfate, filtered and concentrated to give 4- [3- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] as a pale yellow solid ]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]-methyl-amino]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (141mg, 55%, 93% purity).¹H NMR (400MHz, dimethylsulfoxide-d)₆)8.40(q, J ═ 4.2, 3.6Hz, 1H), 8.16-8.06(M, 1H), 7.79-7.67(M, 2H), 7.22(d, J ═ 7.3Hz, 1H), 6.92(d, J ═ 8.7Hz, 1H), 6.22-6.14(M, 1H), 4.35(t, J ═ 7.0 Hz, 2H), 3.49(dd, J ═ 32.6, 9.1Hz, 3H), 3.03(s, 3H), 2.71(t, J ═ 10.5Hz, 1H), 2.10 (q, J ═ 7.3Hz, 3H), 2.00(s, 2H), 1.85-1.66(M, 1H), 1.50(q, J ═ 7.43, 1H, 31.84, 31.83, 31H), 5H, 31.83 (M, M ═ 8.06(M, 1H), 5H), 3.7, 3H), 3.7, 3H, 1H, 18, 1, 5H, 18, 1H⁺(ii) a Retention time: 2.52min (LC method B).

And 4, step 4: 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-3-yl) propyl-methyl-amino ] -2-pyridinyl ] sulfonyl ] -6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide

To 4- [3- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Ammonia sulphurAcyl radical]-2-pyridyl]-methyl-amino]Propyl radical]To a solution of tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (141mg, 0.168mmol, 93% purity) in dichloromethane (2mL) was added trifluoroacetic acid (1.390g, 939.2 μ L, 12.19 mmol). The reaction was stirred at room temperature for 2h and then the mixture was concentrated to dryness. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-3-yl) propyl-methyl-amino ]-2-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (100mg, 48%). ESI-MS M/z calculated 683.2268, Experimental 684.32(M +1)⁺(ii) a Retention time: 1.72min (LC method B).

And 5: 12, 12, 18-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 133)

2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-3-yl) propyl-methyl-amino]-2-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (83mg, 0.1213 mmol), potassium carbonate (100mg, 0.7236mmol), cesium fluoride (22mg, 0.1448mmol) and a small amount

A mixture of molecular sieves in dimethylsulfoxide (4mL) was capped and heated to 165 ℃ for 4 h. The mixture was then cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution and brine. The organic phase was dried (sodium sulfate), filtered and concentrated to an orange oil which was purified by silica gel chromatography with a gentle gradient of 100% dichloromethane to 20% methanol/dichloromethane to give 12, 12, 18-trimethyl-8- (3- {2- [1- (2- [ 1-) (dichloromethane) as a white solid Trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 133) (32.9mg, 42%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)8.22(d, J ═ 2.8Hz, 1H), 7.78(dd, J ═ 12.5, 8.0Hz, 2H), 7.19(d, J ═ 7.3Hz, 1H), 6.91(t, J ═ 8.2Hz, 2H), 6.12(d, J ═ 2.7Hz, 1H), 4.52(s, 1H), 4.32(t, J ═ 7.0Hz, 2H), 3.14(M, 1H), 2.92(M, 4H), 2.70(d, J ═ 17.7Hz, 1H), 2.08(M, J ═ 7.1Hz, 3H), 1.94-1.75(M, 1H), 1.61(s, 3H), 1.49(M, J ═ 13.1, 5H), 1.34(M, 34H), 1.84 (M, 1H), 1.83-1.84 (M, M ═ 3H), 1, 1.84 (M, M ═ 3H), calculated values (M, M ═ 3H), 1H), and calculated values (⁺(ii) a Retention time: 2.29min (LC method B).

Example 37: preparation of 8- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracosane-1 (23), 5(10), 6, 8, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 136) and 8- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl ]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracosane-1 (23), 5(10), 6, 8, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 137)

Step 1: 8- [3- (3, 3-Dicyclopropylpropoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracosane-1 (23), 5(10), 6, 8, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 136) and 8- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracos-1 (23), 5(10), 6, 8, 20(24), 21-hexaen-2,2, 4-trione (enantiomer 2) (compound 137)

Racemic 8- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl ] was chromatographed by SFC using a Phenomenex LUX-4 (250X 21.2mm) column, 5 μm particle size and 60% methanol, 40% carbon dioxide mobile phase (70mL/min over 8.0min) (injection volume 500 μ L, about 30mg/mL in methanol acetonitrile dimethyl sulfoxide (40: 20))]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ] ]The tetracosane-1 (23), 5(10), 6, 8, 20(24), 21-hexaen-2, 2, 4-trione (115mg) was subjected to chiral separation to give 8- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl as a white solid of the first enantiomer to be eluted]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracosane-1 (23), 5(10), 6, 8, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 136) (34.1mg, 29%); 1H NMR (400MHz, chloroform-d) 14.55(s, 1H), 8.47 (d, J ═ 8.6Hz, 1H), 8.16(d, J ═ 33.0Hz, 1H), 7.68(s, 1H), 7.53-7.39(m, 2H), 6.45 (d, J ═ 7.9Hz, 1H), 5.96(d, J ═ 2.8Hz, 1H), 4.77(s, 1H), 4.44(t, J ═ 6.8Hz, 2H), 4.16(d, J ═ 64.7Hz, 1H), 3.36(s, 1H), 3.20-2.90(m, 1H), 2.38(d, J ═ 8.1Hz, 2H), 1.97(q, J ═ 6.8, 3H), 1.20-2.90 (m, 1H), 2.38(d, J ═ 8.1Hz, 2H), 1.97(q, J ═ 6.8, 3H), 1H, 0.29, 0.72 (s, 0.15H), 0.15 (m, 0.13H), 3.15 (m, 0.13H), 3.52H), 4.13H, 3.15 (m, 2H), 1H) 0.23-0.16(M, 2H), 0.10(dt, J ═ 9.4, 4.5Hz, 2H), ESI-MS M/z calculated 619.29407, experimental 620.17(M +1) ⁺(ii) a Retention time: 1.82min (LC method B) and 8- [3- (3, 3-Dicyclopropylpropoxy) -1H-pyrazol-1-yl as white solid as second enantiomer to be eluted]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracos-1 (23), 5(10), 6, 8, 20(24), 21-hexaene-2, 2, 4-Trione (enantiomer 2) (compound 137) (24.5mg, 17%);¹h NMR (400MHz, chloroform-d) 14.55(s, 1H), 8.47(d, J ═ 8.6Hz, 1H), 8.16(d, J ═ 32.4Hz, 1H), 7.68(s, 1H), 7.52-7.40(m, 2H), 6.45(d, J ═ 8.0Hz, 1H), 5.96(d, J ═ 2.8Hz, 1H), 4.77(s, 1H), 4.44(t, J ═ 6.8Hz, 2H), 4.16(d, J ═ 70.4Hz, 1H), 3.49(s, 1H), 3.03(d, J ═ 51.3Hz, 1H), 1.97(q, J ═ 6.8, 2H), 1.72(s, 2H), 1.56(s, 4.27 (s, 1H), 3.27 (d, J ═ 51.3Hz, 1H), 1H, 15.27 (m ═ 6.8, 2H), 15.15.15H, 15H, 15.15 (m ═ 0, 15H, 15H, 2H) 0.15-0.05(M, 2H), ESI-MS M/z calculated 619.29407, Experimental 620.17(M +1)⁺(ii) a Retention time: 1.82min (LC method B).

Example 38: preparation of (14S) -8- [3- (4, 4-dimethylpentyl) -2-oxopyrrolidin-1-yl ]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 145) and (14S) -8- [3- (4, 4-dimethylpentyl) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 146)

Step 1: (14S) -8- [3- (4, 4-dimethylpentyl) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 145) and (14S) -8- [3- (4, 4-dimethylpentyl) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereoisomers)2) (Compound 146)

A4 mL vial was charged with (14S) -8-chloro-12, 12-dimethyl-2. lambda ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (148mg, 0.3181 mmol), 3- (4, 4-dimethylpentyl) pyrrolidin-2-one (86mg, 0.4692mmol), Pd₂(dba)₃(92mg, 0.1005mmol), Xantphos (58mg, 0.1002mmol), cesium carbonate (623mg, 1.912mmol) and anhydrous dioxane (3mL) the mixture was sparged with nitrogen for 2min, capped and stirred at 120 ℃ for 21h. The crude reaction mixture was purified by column chromatography on silica gel (gradient 0% to 5% methanol in dichloromethane) to give 54mg of the product as a mixture of diastereomers, i.e. an off-white solid. The mixture of diastereomers was purified by chiral SFC using ChiralCel OJ-H (250 x 10mm column, 5 μm particle size) and 18% acetonitrile/methanol (90: 10; no modifier)/82% carbon dioxide mobile phase (10mL/min over 10.0min) (injection volume 70 μ L, 24mg/mL solution in methanol: dimethylsulfoxide (90: 10)) to give (14S) -8- [3- (4, 4-dimethylpentyl) -2-oxopyrrolidin-1-yl as the first diastereomer to be eluted ]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 145) (19mg, 10%);¹h NMR (400MHz, dimethylsulfoxide-d)₆)12.38(s, 1H), 7.67(d, J ═ 8.4Hz, 1H), 7.57(t, J ═ 7.8Hz, 1H), 7.52(d, J ═ 8.4Hz, 1H), 7.04(d, J ═ 7.2Hz, 1H), 6.96 (wide d, J ═ 8.0Hz, 1H), 6.70(d, J ═ 8.5 Hz, 1H), 4.05(t, J ═ 9.4Hz, 1H), 3.91 (wide d, J ═ 10.7Hz, 1H), 3.75(q, J ═ 9.3, 8.7Hz, 1H), 3.11 (brs, 1H), 2.94 (brd, J ═ 13.3Hz, 1H), 2.82-2.56 (m), 2.17.87 (1H), 1.6.87 (br, 1H), 1.6.6.6.2.2.2H, 1H, 2.6.7(m, 4H), 1.64-1.41(m, 9H), 1.41-1.27(m, 4H), 1.25-1.13(m, 2H), 0.87(s, 9H). ESI-MS M/z calculated 596.31445, Experimental 597.3 (M +1)⁺(ii) a Retention time: 2.32min (LC method B), and (14S) -8- [3- (4, 4-dimethylpentyl) -2-oxopyrrolidin-1-yl group as the second diastereomer to be eluted]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 146) (15mg, 8%); ¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.41(s, 1H), 7.68(d, J ═ 8.5Hz, 1H), 7.61-7.50(m, 2H), 7.03(d, J ═ 7.2 Hz, 1H), 6.92(d, J ═ 27.7Hz, 1H), 6.69(d, J ═ 8.5Hz, 1H), 3.94(t, J ═ 9.4Hz, 2H), 3.82(q, J ═ 9.1Hz, 1H), 3.09(s, 1H), 2.93(d, J ═ 13.3Hz, 1H), 2.68(t, J ═ 10.9Hz, 2H), 2.25(q, J ═ 8.8Hz, 1H), 2.08(d, J ═ 8.3, 1H), 1.86-1.63 (m), 4.4H, 4 (H), 4.46H), 4.4.4H, 4H, 4.46H, 4H, 1H, 4H, 1H, 4H, 4.46H, 4H, 1H, 4H, 1H, 4; ESI-MS M/z calculated 596.31445, Experimental 597.3(M +1)⁺(ii) a Retention time: 2.33min (LC method B).

Example 39: preparation of 12, 12, 22-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 148) and 12, 12, 22-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 149)

Step 1: 12, 12, 22-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 148) and 12, 12, 22-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 149)

To racemic 12, 12, 22-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (85mg, 0.1299mmol) was subjected to chiral SFC chromatography using the following SFC protocol: ChiralPak AS-3 (150X 2.1mm), 3 μm; 35 ℃ mobile phase: 30% acetonitrile: methanol (90: 10), 70% carbon dioxide. The first enantiomer to be eluted was 12, 12, 22-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] isomer ]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 148) (34mg, 40%). ESI-MS M/z calculated 647.2502, Experimental 648.34(M +1)⁺(ii) a Retention time: 2.24min (LC method B). The second enantiomer to be eluted was 12, 12, 22-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] isomer]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 149) (35mg, 41%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.46(s，1H)，8.23(d，J＝2.8Hz，1H)，7.83(d，J＝8.2Hz，1H)，7.41(d，J ＝8.5Hz，1H)，6.93(d，J＝8.2Hz，1H)，6.65(d，J＝8.6Hz, 2H), 6.12(d, J ═ 2.7Hz, 1H), 4.32(t, J ═ 7.0Hz, 2H), 4.00-3.79(m, 1H), 3.27-3.14(m, 1H), 2.93(d, J ═ 13.2Hz, 1H), 2.84(t, J ═ 10.5Hz, 1H), 2.36(s, 3H), 2.08(t, J ═ 7.1Hz, 2H), 1.87(dd, J ═ 11.6, 5.2Hz, 1H), 1.77(m, 1H), 1.57(d, J ═ 35.9Hz, 8H), 1.44-1.29(m, 1H), 0.96(d, J ═ 4.4, 2H), 0.91(d, J ═ 2H), 13.13H, 3H). ESI-MS M/z calculated 647.2502, Experimental 648.34(M +1) ⁺(ii) a Retention time: 2.25min (LC method B).

Example 40: preparation of 4- [3- (3, 3-Dicyclopropylpropoxy) -1H-pyrazol-1-yl]-20, 20-dimethyl-10. lambda.⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]

Docosac

2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (enantiomer 1) (compound 153) and 4- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl]-20, 20-dimethyl-10. lambda.⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]

Docosac

2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (enantiomer 2) (compound 154)

Step 1: 4- [3- [3- [ [ 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] pyrazol-1-yl ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (521mg, 1.440 mmol) and carbonyldiimidazole (237mg, 1.462mmol) were combined in tetrahydrofuran (5.0mL) and stirred at room temperature for 2 h. Subsequently, 2-dimethyl-4- [3- (3-sulfamoylpyrazol-1-yl) propyl ] is added]Pyrrolidine-1-carboxylic acid tert-butyl ester (460mg, 1.190mmol) followed by addition of 1, 8-diazabicyclo [5.4.0 ]Undec-7-ene (280. mu.L, 1.872mmol) and the reaction stirred at room temperature for 18 h. Will be provided withThe reaction was diluted with ethyl acetate and washed with a saturated solution of ammonium chloride followed by brine the organics were separated, dried over sodium sulfate, filtered and evaporated the residue was purified by silica gel chromatography using a gradient of 100% dichloromethane to 20% methanol/dichloromethane to give 4- [3- [3- [ [ 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl ] as a white solid]Pyridine-3-carbonyl]Sulfamoyl radical]Pyrazol-1-yl]Propyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (270mg, 31%).¹H NMR (400MHz, chloroform-d) 9.61(d, J ═ 95.1Hz, 1H), 8.30(d, J ═ 2.9Hz, 1H), 8.24(t, J ═ 8.9Hz, 1H), 7.75(d, J ═ 8.4Hz, 1H), 7.47(d, J ═ 2.6Hz, 1H), 7.05(d, J ═ 2.3Hz, 1H), 5.97(d, J ═ 2.9Hz, 1H), 4.43(t, J ═ 6.8Hz, 2H), 4.20(t, J ═ 7.1Hz, 2H), 3.78-3.54(m, 1H), 2.84(t, J ═ 10.1, 1H), 2.07(s, 1H), 1.97(q, 6.8, 1H), 3.81-3.54 (m, 1H), 3.84 (t, 1H), 3.7.7, 3(t, 3H), 3, 1H), 3(t, 3, 1H), 3 (q, 3, 1H), 3(t, 3, 1H), 3 (q, 3, 1H), 3, 6.8Hz, 1H), 0.20(dtd, J ═ 8.2, 4.9, 3.5Hz, 2H), 0.10(ddd, J ═ 9.3, 4.8, 3.5Hz, 2H), ESI-MS M/z calculated 729.30756, experimental 730.4(M +1) ⁺(ii) a Retention time: 0.92min (LC method A).

Step 2: 4- [3- (3, 3-Dicyclopropylpropoxy) -1H-pyrazol-1-yl]-20, 20-dimethyl-10. lambda.⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]

Docosac

2, 4, 6, 11(22), 12-pentaen-8, 10, 10-triones

4- [3- [3- [ [ 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl ] is reacted at room temperature]Pyridine-3-carbonyl]Sulfamoyl radical]Pyrazol-1-yl]Propyl radical]A solution of tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (270mg, 0.3697mmol) in dichloromethane (1.862mL) and trifluoroacetic acid (300. mu.L, 3.920mmol) was stirred for 4 h. The solvent was then removed in vacuo. The residue was dissolved in ethyl acetate, washed with 2mL of saturated sodium bicarbonate solution and the solvent was evaporatedThe residue was dissolved in dimethyl sulfoxide (5.586mL) and added

Molecular sieves, and the reaction mixture was stirred for 10 min. Subsequently, cesium fluoride (171mg, 1.126mmol) and potassium carbonate (158 mg, 1.143mmol) were added, and the reaction mixture was heated at 150 ℃ overnight. The reaction mixture was filtered through Whatman filter disc (puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS method using a double gradient run of 50-99% mobile phase B over 15.0min (mobile phase a ═ water (0.05% hydrochloric acid), mobile phase B ═ acetonitrile) to give rac 4- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl as a white solid ]-20, 20-dimethyl-10. lambda.⁶Thia-1, 3, 9, 14, 22 pentaazatetracyclo [16.2.1.111, 14.02, 7]

Docosac

2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (50mg, 23%). ESI-MS M/z calculated 593.27844, Experimental 594.4 (M +1)⁺(ii) a Retention time: 2.36min (LC method B).

And step 3: 4- [3- (3, 3-Dicyclopropylpropoxy) -1H-pyrazol-1-yl]-20, 20-dimethyl-10. lambda.⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]

Docosac

2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (enantiomer 2) (compound 154)

Racemic 4- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl ] was chromatographed by SFC using a ChiralPak AS-H (250 × 10mm) column, 5 μm particle size) and a 28% acetonitrile/methanol (90: 10)/72% carbon dioxide mobile phase (10mL/min over 8.0min) (70 μ L injection volume of about 24mg/mL solution in acetonitrile/methanol/dimethylsulfoxide (82: 8: 10) ]-20, 20-dimethyl-10. lambda.⁶-a source of-sulfur-1,3, 9, 14, 22 pentaazatetracyclo [16.2.1.111, 14.02, 7]The

docosate

2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (50mg) was subjected to chiral separation to give 4- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl as the first enantiomer to be eluted]-20, 20-dimethyl-10. lambda.⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac 2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (enantiomer 1) (compound 153) (20mg, 18%);¹h NMR (400MHz, chloroform-d) 8.63(s, 1H), 8.17(d, J ═ 2.7Hz, 1H), 7.67(d, J ═ 8.3 Hz, 1H), 7.47(d, J ═ 2.3Hz, 1H), 7.07(d, J ═ 2.3Hz, 1H), 7.02(d, J ═ 8.2Hz, 1H), 5.87(d, J ═ 2.7Hz, 1H), 4.42(t, J ═ 6.8Hz, 2H), 4.33(dt, J ═ 13.3, 3.4Hz, 1H), 4.00-3.85 (m, 1H), 2.74(t, J ═ 8.1Hz, 1H), 2.12(ttd, J ═ 14.6, 10.0, 8.0, 7.01, 2.81H), 1H (m, 1H), 2.71H, 71H, 1H, 71H, 1H, 71H, 0.7.7H, 1H, 71H, 7H, and 71H, 4H) 0.37-0.30(M, 1H), 0.24-0.15(M, 2H), 0.15-0.07(M, 2H), ESI-MS M/z calculated 593.27844, experimental 594.4(M +1) ⁺(ii) a Retention time: 2.39min (LC method B) and 4- [3- (3, 3-Dicyclopropylpropoxy) -1H-pyrazol-1-yl as white solid as second enantiomer to be eluted]-20, 20-dimethyl-10. lambda.⁶Thia-1, 3, 9, 14, 22 pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac 2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (enantiomer 2) (compound 154) (23.6mg, 47%);¹h NMR (400 MHz chloroform-d) 8.16(d, J ═ 2.7Hz, 1H), 7.65(d, J ═ 8.3Hz, 1H), 7.46(d, J ═ 2.4Hz, 1H), 7.06(d, J ═ 2.3Hz, 1H), 7.00(d, J ═ 8.3Hz, 1H), 5.87(d, J ═ 2.7Hz, 1H), 4.42 (t, J ═ 6.8Hz, 2H), 4.32(d, J ═ 13.5Hz, 1H), 4.00-3.83(m, 1H), 2.73(t, J ═ 8.1Hz, 1H), 2.23-2.09(m, 2H), 1.97(q, J ═ 6.9, 3H), 1.74H, 1, 9, 5 (ddh), 1.5, 8.1Hz, 1H), 1H), 2.23-2.09(m, 2H), 1.97(q, J ═ 6.9, 3.9, 3H), 3.74 (ddh), 0, 5H, 1H), 7.7.7, 1H, 7, 7.7, 7, 7.7.7, 7H), 7H, 7, 7.6.6, 7H), 0.38-0.30(m, 1H), 0.25-0.18(m, 2H), 0.12(ddtd, J ═ 11.4, 5.2, 3.7, 3.1, 1.9Hz, 2H.) ESI-MS M/z calculated 593.27844, experimental 594.4(M +1)⁺(ii) a Retention time: 2.39min (LC method B).

Example 41: preparation of 12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl [ ]]Propoxy } -1H-pyrazol-1-yl) -15-oxa-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 159) and 12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) -15-oxa-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 160)

Step 1: methanesulfonic acid 2- [1- (trifluoromethyl) cyclopropyl ] ethyl ester

A1000 mL 3-neck round bottom flask was equipped with a mechanical stirrer, cooling bath, J-Kem temperature probe, addition funnel, and nitrogen inlet/outlet. Charging 2- [1- (trifluoromethyl) cyclopropyl ] into a vessel under a nitrogen atmosphere]Ethanol (125g, 811.0mmol) and 2-methyltetrahydrofuran (625mL) to provide a clear colorless solution. Stirring was started and the pot temperature was recorded as 19 ℃. The vessel was then charged with triethylamine (124.3mL, 891.8mmol) and added in one portion without doping. The cooling bath was then charged with crushed ice/water and the pot temperature was lowered to 0 ℃. The addition funnel was charged with a solution of methanesulfonyl chloride (62.77mL, 811.0mmol) in 2-methyltetrahydrofuran (125mL, 2mL/g), which was then passed through 90mi n was added dropwise, yielding a white suspension and allowing the exotherm to 1 ℃. The mixture was allowed to slowly warm to room temperature and stirring was continued at room temperature for 1h, at which time the mixture was poured into ice-cold water (250mL) and then transferred to a separatory funnel. The organics were removed and washed with 20 wt% potassium bicarbonate solution (250mL), dried over sodium sulfate (200g) and then filtered through a glass frit buchner funnel. The clear filtrate was concentrated under reduced pressure to provide methanesulfonic acid 2- [1- (trifluoromethyl) cyclopropyl ] as a clear pale yellow oil]Ethyl ester (185g, 98%).¹H NMR (400MHz, chloroform-d) 4.36(ddt, J ═ 7.1, 6.4, 0.7Hz, 2H), 3.02 (s, 3H), 2.03(t, J ═ 7.1Hz, 2H), 1.11-0.98(m, 2H), 0.81-0.66(m, 2H).

Step 2: 3- [1- (trifluoromethyl) cyclopropyl ] propionitrile

A1000 mL 3-necked round bottom flask was equipped with a mechanical stirrer, heating mantle, J-Kem temperature probe/controller, water-cooled reflux condenser, and nitrogen inlet/outlet, and 2- [1- (trifluoromethyl) cyclopropyl ] methanesulfonate was charged to the vessel under a nitrogen atmosphere]Ethyl ester (50g, 215.3mmol) and dimethyl sulfoxide (250mL) to provide a clear pale yellow solution stirring was started and the pot temperature was recorded as 19 ℃. The vessel was charged with sodium cyanide (13.19g, 269.1mmol), added in one portion as a solid the mixture was heated to a pot temperature of 70 ℃ and the conditions were maintained for 24h after heating all the sodium cyanide dissolved and the reaction mixture became a light amber suspension after cooling to room temperature, the reaction mixture was poured into water (500mL) and then transferred to a separatory funnel and partitioned with methyl tert-butyl ether (500mL), the organics were removed and the residual aqueous solution was extracted with methyl tert-butyl ether (3 x 250mL) the combined organic layers were washed with water (2 x 250mL), dried over sodium sulfate (200g) and then filtered through a glass frit buchner funnel. The clear filtrate was concentrated under reduced pressure to provide 3- [1- (trifluoromethyl) cyclopropyl ] as a clear amber oil ]Propionitrile (30g, 85%).¹H NMR (400MHz, chloroform-d) 2.55(t, J ═ 7.6Hz, 2H), 1.93(t, J ═ 7.7Hz,2H)，1.11-1.04(m，2H)，0.78-0.70(m，2H).

and step 3: 3- [1- (trifluoromethyl) cyclopropyl ] propanoic acid

A1000 mL 3-neck round bottom flask was equipped with a mechanical stirrer, heating mantle, J-Kem temperature probe/controller, water-cooled reflux condenser, and nitrogen inlet/outlet, then the vessel was charged with 3- [1- (trifluoromethyl) cyclopropyl ] under a nitrogen atmosphere]Propionitrile (25g, 153.2mmol) and ethanol (375mL) to provide a clear amber solution. Stirring was started and the pot temperature was recorded as 19 ℃. The vessel was then charged with sodium hydroxide (102.1mL, 6M, 612.6mmol) and added all at once. The resulting clear amber solution was heated to a pot temperature of 70 ℃ and the conditions were maintained for 24 h. After cooling to room temperature, the reaction mixture was concentrated to remove ethanol. The residual aqueous solution was diluted with water (150mL) and then transferred to a separatory funnel and partitioned with methyl tert-butyl ether (50 mL.) the aqueous phase was removed and the pH adjusted to about pH 1 with 6M hydrochloric acid solution. The resulting aqueous solution was transferred to a separatory funnel and partitioned with methyl tert-butyl ether (250 mL). The organics were removed and the residual aqueous solution was extracted with methyl tert-butyl ether (2X 150 mL.) the combined organics were dried over sodium sulfate (150g) and then filtered through a frit Buchner funnel. The clear filtrate was concentrated under reduced pressure to provide 3- [1- (trifluoromethyl) cyclopropyl ] as a clear amber oil ]Propionic acid (26g, 93%).¹H NMR (400MHz, chloroform-d) 2.63-2.50 (m, 2H), 1.96-1.84(m, 2H), 1.03-0.95(m, 2H), 0.66-0.58(m, J ═ 1.7Hz, 2H).

And 4, step 4: 3- [1- (trifluoromethyl) cyclopropyl ] propan-1-ol

A1000 mL 3-neck round bottom flask was equipped with a mechanical stirrer, cooling bath, addition funnel, J-Kem temperature probe, and nitrogen inlet/outletLithium aluminium pellets (6.775g, 178.5 mmol) were then charged to the vessel under nitrogen (250mL), stirring was started and the pot temperature recorded at 20 ℃. the mixture was stirred at room temperature for 0.5h to dissolve the pellets, the pot temperature of the resulting grey suspension was recorded at 24 ℃. the cooling bath was then charged with crushed ice/water and the pot temperature was allowed to fall to 0 ℃. the addition funnel was charged with 3- [1- (trifluoromethyl) cyclopropyl]A solution of propionic acid (25g, 137.3mmol) in tetrahydrofuran (75mL, 3mL/g) and the clear pale yellow solution was added dropwise over 1h after the addition was complete, the pot temperature of the resulting dark brown suspension was recorded as 5 ℃. The suspension was cooled to 0 ℃ with a crushed ice/water cooling bath and then quenched by very slow dropwise addition of water (6.775mL), followed by addition of 15 wt% sodium hydroxide solution (6.775mL) and then finally water (20.32 mL.) the pot temperature of the resulting white suspension was recorded as 5 ℃. The suspension was stirred for a further 30min at about 5 ℃ and subsequently filtered through a frit buchner funnel with a 20mm layer of celite. The filter cake was displacement washed with tetrahydrofuran (2X 150mL) and subsequently dried in vacuo for 15 min. The filtrate was dried over sodium sulfate (250g) and then filtered through a glass frit Buchner funnel the filtrate was concentrated under reduced pressure to provide a clear light amber colored oil as the desired product, i.e., 3- [1- (trifluoromethyl) cyclopropyl ]Propan-1-ol (21.2g, 92%).¹H NMR (400MHz, chloroform-d) 3.65(t, J ═ 6.0Hz, 2H), 1.78-1.59(m, 4H), 0.99-0.91(m, 2H), 0.59(dp, J ═ 4.7, 1.7Hz, 2H).

And 5: 3- [3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazole-1-carboxylic acid tert-butyl ester

A5000 mL 3-neck round bottom flask was equipped with a mechanical stirrer, heating mantle, J-Kem temperature probe/controller, addition funnel, water-cooled reflux condenser, and nitrogen inlet/outlet.A vessel was charged with tert-butyl 5-oxo-1H-pyrazole-2-carboxylate (175g, 950.1mmol) and tetrahydrofuran (2100mL) under a nitrogen atmosphere to provide a clear pale yellow solutionThe pot temperature was recorded as 19 ℃. Subsequently charging the vessel with 3- [1- (trifluoromethyl) cyclopropyl]Propan-1-ol (175.7g, 1.045mol), which was added in one portion without doping, was then charged with triphenylphosphine (274.1g, 1.045mol), which was added in one portion as a solid. The resulting clear pale yellow solution was then treated with 2h undoped dropwise added diisopropyl azodicarboxylate (205.7mL, 1.045mol) causing a gradual exotherm to 40 ℃ and a clear pale amber solution to result. The reaction mixture was then heated to a pot temperature of 50 ℃ and the conditions were maintained for 2h the clear amber reaction mixture was concentrated under reduced pressure and the resulting clear dark amber oil was suspended in toluene (1400mL) and stirred at room temperature for 1h during which time solid triphenylphosphine oxide precipitated. The desired fractions were combined and concentrated under reduced pressure to provide 3- [3- [1- (trifluoromethyl) cyclopropyl ] as a clear pale yellow oil ]Propoxy group]Pyrazole-1-carboxylic acid tert-butyl ester (280g, 88%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)8.07(d，J＝3.0Hz，1H)，6.09(d，J＝2.9 Hz，1H)，4.15(t，J＝6.2Hz，2H)，1.91-1.75(m，2H)，1.76-1.63(m，2H)，1.55(s， 9H)，0.98-0.84(m，2H)，0.74(dt，J＝3.3，1.9Hz，2H)。

Step 6: 3- [3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] -1H-pyrazole

A5000 mL 3-necked round bottom flask was equipped with a mechanical stirrer, heating mantle, J-Kem temperature probe/controller, water-cooled reflux condenser, addition funnel, and nitrogen inlet/outlet.A vessel was charged with 3- [3- [1- (trifluoromethyl) cyclopropyl ] under a nitrogen atmosphere]Propoxy group]Pyrazole-1-carboxylic acid tert-butyl ester (280g, 837.5mmol), dichloromethane (840mL), and methanol (840mL) to provide a clear pale yellow colorA colored solution. Stirring was started and the pot temperature was recorded as 19 ℃. the addition funnel was charged with 1, 4-dioxane containing hydrogen chloride (628mL, 4M, 2.512mol), which was then added dropwise over 2h, causing a gradual exotherm to 30 ℃. The resulting clear pale yellow solution was heated to a pot temperature of 45 ℃ and the conditions were maintained for 1h. The remaining residue was dissolved in methyl tert-butyl ether (2.24L) and subsequently transferred to a separatory funnel and partitioned with ice cold sodium hydroxide (1.256L, 2M, 2.512 mol). The organics were removed and the residual aqueous solution was extracted with tert-butyl methyl ether (2X 500 mL.) the combined organics were washed with a saturated solution of sodium chloride (2X 500mL), dried over sodium sulfate (500g) and then filtered through a glass frit Buchner funnel the clear pale yellow filtrate was concentrated under reduced pressure to provide 3- [3- [1- (trifluoromethyl) cyclopropyl as a clear pale yellow oil ]Propoxy group]ESI-MS M/z calculated 234.09799, Experimental 235.1(M +1) — 1H-pyrazole (190g, 97%)⁺(ii) a Retention time: 1.37min (LC method B).

And 7: 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carboxylic acid tert-butyl ester

A5000 mL 3-neck round bottom flask was equipped with a mechanical stirrer, a cooling bath as an auxiliary containment, a J-Kem temperature probe, a water-cooled reflux condenser, an addition funnel, and a nitrogen inlet/outlet. Charging 3- [3- [1- (trifluoromethyl) cyclopropyl ] into a vessel under a nitrogen atmosphere]Propoxy group]-1H-pyrazole (188.8g, 806.1mmol) and N, N-dimethylformamide (2.40L), providing a clear pale yellow solution. Stirring was started and the pot temperature was recorded as 17 ℃. The vessel was then charged with tert-butyl 2, 6-dichloropyridine-3-carboxylate (200g, 806.1mmol) and added as a solid in one portion. The resulting clear pale yellow solution was then treated with potassium carbonate (144.8g, 1.048mol) added in one portion as a solid, followed by 1, 4-diazabicyclo [2.2.2 ] added in one portion as a solid]Octane (13.56g, 120.9mmol) the resulting pale yellow suspension was stirred at room temperatureStir 24h. cool the reaction mixture to 10 ℃ with a crushed ice/water cooling bath. The addition funnel was charged with water (2.40L) which was added dropwise over 2h and resulted in a thick suspension and an exotherm to 15 ℃. The resulting suspension was stirred for a further 30 min at 15 ℃ and subsequently filtered through a frit buchner funnel. The filter cake was displacement washed with water (3X 500mL) and then dried in vacuo in a Buhner funnel for 2 h. The material was then allowed to air dry overnight to provide 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] as a white particulate solid ]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (305g, 85%). This material was used in the next synthetic step without further purification. ESI-MS M/z calculated 445.138, Experimental 446.2(M +1)⁺(ii) a Retention time: 2.54min (LC method B).

And 8: 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carboxylic acid

A1000 mL 3-neck round bottom flask was equipped with a mechanical stirrer, heating mantle, J-Kem temperature probe/controller, addition funnel, water-cooled reflux condenser, and nitrogen inlet/outlet the vessel was charged with 2-chloro-6- [3- [1- (trifluoromethyl) cyclopropyl ] under a nitrogen atmosphere]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (50g, 112.1 mmol) and 2-propanol (250mL) to provide an off-white suspension. Start stirring and pot temperature recorded as 19 ℃ add hydrochloric acid (93.42mL, 6M, 560.5mmol) to the addition funnel which adds dropwise over 30min and causes exotherm to 30 ℃ then heat the resulting suspension to reflux (pot temperature about 82 ℃). after heating, the suspension becomes a clear pale yellow solution (at this point the pot temperature about 75 ℃). after stirring under reflux for about 30min the solid starts to precipitate after continuing to stir the suspension under reflux for another 30min, at this point water (150 mL) is added dropwise over 45min then heat is removed and the suspension continues to stir and slowly cool to room temperature the material is collected in a glass frit buchner funnel by vacuum filtration and the filter cake is displacement washed with 1: 1 water/2-propanol (250mL), then water (2 × 250mL) and then vacuum dried in the buchner funnel Drying for 30 min. The material was further dried in a vacuum oven at 45 ℃ for 24h to provide 2-chloro-6- [3- [1- (trifluoromethyl) cyclopropyl ] 3- [3- (trifluoromethyl) propyl ] as a white solid]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxylic acid (41.5g, 95%).¹H NMR (400MHz, dimethylsulfoxide-d)₆) 13.59(s，1H)，8.50-8.28(m，2H)，7.72(d，J＝8.4Hz，1H)，6.20(d，J＝3.0Hz，1H)， 4.23(t，J＝6.2Hz，2H)，1.86(dq，J＝10.8，6.3Hz，2H)，1.78-1.66(m，2H)，0.98- 0.87(m，2H)，0.76(dt，J＝4.9，1.7Hz，2H).

And step 9: 2, 2-dimethyl-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester

Di-tert-butyl dicarbonate (22.9g, 24.11mL, 104.9mmol) is added to a solution of 5, 5-dimethylpyrrolidin-3-one (hydrochloride) (13.08g, 87.42mmol), triethylamine (17.71g, 24.4mL, 175.0mmol) and DMAP (1.1g, 9.004mmol) in dichloromethane (325mL) and the reaction mixture is stirred at room temperature overnight. The reaction mixture was washed with 1N hydrochloric acid (300mL), and the aqueous layer was extracted with dichloromethane (2X 250 mL). The organic layers were combined, washed with 5% sodium bicarbonate (250mL) and brine (150mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 2, 2-dimethyl-4-oxo-pyrrolidine-1-carboxylate (18.5g, 99%) as a white solid.¹H NMR(300MHz，CDCl₃) ppm 1.33-1.66(M, 15H), 2.51(s, 2H), 3.85(br.s., 2H). ESI-MS M/z calculated 213.27, experimental 158.2(M-C4H8)⁺(ii) a Retention time: 1.91min (LC method I).

Step 10: 4-hydroxy-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2, 2-dimethyl-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (150mg, 0.7033mmol) was dissolved in anhydrous methanol (2.5mL) and cooled in an ice bath₄(30mg, 0.7930mmol) and the reaction mixture was stirred at 0 ℃ for 1.5 h.diluted with water (25mL) and 1M aqueous hydrochloric acid (0.5 mL.) the aqueous layer was extracted with ethyl acetate (2X 25mL) and the organic layers were combined, washed with brine (10mL), dried over sodium sulfate, filtered and concentrated in vacuo to give tert-butyl 4-hydroxy-2, 2-dimethyl-pyrrolidine-1-carboxylate (150mg, 99%) which was used directly in the subsequent step ESI-MS M/z calculated 215.15215, experimental 216.2(M +1)⁺(ii) a Retention time: 0.48min (LC method A).

Step 11: 4- (2-hydroxyethoxy) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester:

in a 250mL flask, tert-butyl 4-hydroxy-2, 2-dimethyl-pyrrolidine-1-carboxylate (3g, 13.93mmol) was dissolved in N, N-dimethylformamide (15mL) at 0 ℃, and sodium hydride (1.8g, 60% weight/weight in mineral oil, 45.00mmol) was added carefully, the mixture was stirred at 0 ℃ for 15min, and then 2-bromoethoxy-tert-butyl-dimethyl-silane (9mL, 41.95mmol) was added dropwise at 0 ℃ and the mixture was allowed to warm to room temperature. The mixture was stirred for 16h then the mixture was cooled to 0 ℃, quenched with water and extracted with ether the organic extract was washed with water, dried (sodium sulfate), filtered and concentrated in vacuo. The resulting orange oil was purified by silica gel chromatography, eluting with a gradient of 0-30% ethyl acetate/hexanes to give the tert-butyl (dimethyl) silyl protected intermediate, which was dissolved in tetrahydrofuran (20mL), treated with TBAF (28mL, 1M, 28.00mmol) in tetrahydrofuran and stirred at room temperature for 2 h. The mixture was concentrated, and the residue was dissolved in dichloromethane, washed with water, dried over sodium sulfate, filtered and evaporated in vacuo. The crude material obtained was purified by silica gel chromatography eluting with a gradient of 0-20% methanol in dichloromethane to give tert-butyl 4- (2-hydroxyethoxy) -2, 2-dimethyl-pyrrolidine-1-carboxylate (1.6g, 44% yield). ¹H NMR (400 MHz, chloroform-d) 3.97(d, J ═ 4.0Hz, 1H), 3.80-3.34(m, 6H), 2.05(t, J ═ 6H), and1Hz, 1H), 1.97(d, J ═ 16.4Hz, 2H), 1.52-1.30(M, 15H), ESI-MS M/z calculated 259.17834, experimental 260.17(M +1)⁺(ii) a Retention time: 0.55min (LC method A).

Step 12: 4- (2-azidoethoxy) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of 4- (2-hydroxyethoxy) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.6g, 6.169 mmol) in dichloromethane (20mL) was added triethylamine (5.2mL, 37.31mmol) followed by methanesulfonyl chloride (1.4mL, 18.09mmol) at 0 ℃. The reaction mixture was stirred at room temperature for 20 h.quenched with ice water and dichloromethane and the resulting layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the crude mesylate salt, which was combined with sodium azide (1.2g, 18.46mmol) in N, N-dimethylformamide (10mL) and the mixture was stirred at 50 ℃ for 2 h.the reaction was quenched with water and extracted with ether. ¹H NMR (400MHz, chloroform-d) 3.96(q, J ═ 4.6Hz, 1H), 3.69 to 3.31(m, 6H), 2.06 to 1.91(m, 2H), 1.53 to 1.32(m, 15H).

Step 13: 4- (2-aminoethoxy) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester:

to a solution of 4- (2-azidoethoxy) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.33g, 4.677mmol) in methanol (20mL) was added palladium on carbon (500mg, 10% w/w, 0.4698 mmol). The mixture was saturated with hydrogen and stirred at room temperature for 2h while the reaction mixture was purged with hydrogen. Will be mixed withThe mixture was filtered and evaporated in vacuo to give 4- (2-aminoethoxy) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.188g, 98%).¹H NMR (400MHz, chloroform-d) 4.00-3.87(m, 1H), 3.69-3.35(m, 4H), 2.94-2.71(m, 2H), 2.07-1.83(m, 2H), 1.47(q, J ═ 9.4, 8.4Hz, 15H).

Step 14: 2, 2-dimethyl-4- [2- [ (6-sulfamoyl-2-pyridyl) amino ] ethoxy ] pyrrolidine-1-carboxylic acid tert-butyl ester

In a sealed 20mL microwave vial, a solution of tert-butyl 4- (2-aminoethoxy) -2, 2-dimethyl-pyrrolidine-1-carboxylate (1.188mg, 4.598mmol), 6-fluoropyridine-2-sulfonamide (810mg, 4.598mmol), and diisopropylethylamine (4mL, 22.96mmol) in n-butanol (10mL) is stirred at 150 ℃ for 16h ]Ethoxy radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (1.500 g, 66%). ESI-MS M/z calculated 414.1937, Experimental value 415.3(M +1)⁺(ii) a Retention time: 0.61min (LC method A).

Step 15: 4- [2- [ [6- [ [ 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] ethoxy ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

The mixture was charged with carbonyldiimidazole (208mg, 1.283mmol) and 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]A50 mL flask of pyridine-3-carboxylic acid (500mg, 1.283mmol) was evacuated and back-filled with nitrogen (3X). tetrahydrofuran (8mL) was added and the mixture stirred at 50 ℃ for 1 h. Next, 2-bis was addedMethyl-4- [2- [ (6-sulfamoyl-2-pyridyl) amino group]Ethoxy radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (483mg, 1.165mmol) and 1, 8-diazabicyclo [5.4.0]A solution of undec-7-ene (450mg, 2.956mmol) in tetrahydrofuran (6mL) and the mixture stirred at 50 ℃ overnight the reaction was diluted with ethyl acetate and washed with water the organic phase was dried over sodium sulfate, evaporated in vacuo and purified by chromatography on silica eluting with a 0-50% ethyl acetate/hexane gradient to give some pure fractions ₁₈): gradient of 1-99% acetonitrile in water/hydrochloric acid modifier purification of pooled fractions from the two purifications to give 4- [2- [ [6- [ [ 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] 4- [2- [ [6- [ [ 2-chloro- ] -6- [3- [1- (trifluoromethyl) cyclopropyl ] amino acid]Propoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Ethoxy radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (483mg, 53%). ESI-MS M/z calculated 785.25854, Experimental 786.33(M +1)⁺(ii) a Retention time: 0.88min (LC method A).

Step 16: 2-chloro-N- [6- [2- (5, 5-dimethylpyrrolidin-3-yl) oxyethylamino ] -2-pyridinyl ] sulfonyl ] -6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carboxamide

Reacting 4- [2- [ [6- [ [ 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] group]Propoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Ethoxy radical]A solution of tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (483mg, 0.61mmol) in dioxane (5mL) was treated with dioxane containing hydrochloric acid (6mL, 6M, 36.00mmol) and stirred at room temperature for 2 h. The mixture was evaporated in vacuo and the residue quenched with aqueous sodium bicarbonate. The white precipitate formed was filtered off and washed with ethyl acetate. The aqueous phase was additionally extracted with ethyl acetate, the combined organic extracts were dried over sodium sulfate, filtered and evaporated to another solid product, which was combined with the earlier precipitated solid and dried in vacuo to give 2-chloro-N- [ [6- [2- (5, 5-dimethylpyrrolidin-3-yl) oxyethylamino [ ] -chloro-N- [ [6- [2- (5, 5-dimethylpyrrolidin-3-yl) oxy ] ethyl ] amino ]-2-pyridyl]Sulfonyl radical]-6-[3- [3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxamide (350mg, 83%). ESI-MS M/z calculated 685.2061, Experimental 686.3(M +1)⁺(ii) a Retention time: 0.64min (LC method A).

And step 17: 12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Propoxy } -1H-pyrazol-1-yl) -15-oxa-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione

In a 5mL microwave vial, cesium fluoride (162mg, 1.066mmol), potassium carbonate (367mg, 2.655mmol) and

molecular sieves (300mg) and the vials were evacuated/back-filled with nitrogen. Next, 2-chloro-N- [ [6- [2- (5, 5-dimethylpyrrolidin-3-yl) oxyethylamino ] is added]-2-pyridyl]Sulfonyl radical]-6- [3- [3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]A solution of pyridine-3-carboxamide (360mg, 0.5247 mmol) in dimethylsulfoxide (5mL) and the mixture was stirred at 150 ℃ overnight the mixture was filtered and purified by preparative reverse phase HPLC (C)₁₈): gradient of 1-99% acetonitrile in water/hydrochloric acid modifier (15min) to give 12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl ] methyl ]Propoxy } -1H-pyrazol-1-yl) -15-oxa-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (118.2mg, 34%).¹H NMR (400MHz, chloroform-d) 9.51(s, 1H), 8.16(d, J ═ 2.7Hz, 1H), 7.90(d, J ═ 8.0Hz, 1H), 7.60(t, J ═ 7.8Hz, 1H), 7.52(d, J ═ 7.2Hz, 1H), 7.15(d, J ═ 8.2Hz, 1H), 6.65(d, J ═ 7.3Hz, 1H), 5.90(d, J ═ 2.7Hz, 1H), 4.82(s, 1H), 4.33(d, J ═ 7.1Hz, 1H), 4.24(t, J ═ 6.1Hz, 2H), 4.06(s, 1H), 3.82(t, J ═ 9.5, 1H), 3.58(d, 3.58 Hz, 3.7 Hz, 1H), 3.58(d, 1H).28(m, 2H), 3.15-3.03 (m, 1H), 2.23-2.14(m, 1H), 1.95(dq, J ═ 11.0, 6.3Hz, 3H), 1.75(dd, J ═ 10.0, 6.2Hz, 2H), 1.64(s, 3H), 1.60(s, 3H), 0.99-0.95(m, 2H), 0.60(d, J ═ 4.8Hz, 2H). ESI-MS M/z calculated 649.22943, Experimental 650.29(M +1)⁺(ii) a Retention time: 2.12min (LC method B).

Step 18: 12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Propoxy } -1H-pyrazol-1-yl) -15-oxa-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 159) and 12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) -15-oxa-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 160)

Racemic 12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl ] c-orowas purified by SFC chromatography using ChiralPak AS-H (250 × 21.2mm, 5 μm particle size) and a 28% acetonitrile/methanol (90: 10)/72% carbon dioxide mobile phase (70mL/min over 8.0min) (injection volume 500 μ L, 32mg/mL solution in acetonitrile/methanol (90: 10))]Propoxy } -1H-pyrazol-1-yl) -15-oxa-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]The tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (116mg, 0.18 mmol) was subjected to chiral separation to give 12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl ] ketone as the first enantiomer to be eluted]Propoxy } -1H-pyrazol-1-yl) -15-oxa-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 159) (48.3mg, 28%); ESI-MS M/z calculated 649.22943, Experimental 650.32(M +1)⁺(ii) a RetentionTime: 2.12min (LC method B) and 12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl ] as the second enantiomer to be eluted]Propoxy } -1H-pyrazol-1-yl) -15-oxa-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 160) (56.0mg, 48%);¹h NMR (400MHz, dimethylsulfoxide-d)₆)12.57(s, 1H), 8.19(d, J ═ 2.8Hz, 1H), 7.78(d, J ═ 8.1Hz, 1H), 7.58(t, J ═ 7.7Hz, 1H), 7.09(d, J ═ 7.3Hz, 2H), 6.93(d, J ═ 8.1Hz, 1H), 6.70(d, J ═ 8.3Hz, 1H), 6.11(d, J ═ 2.7Hz, 1H), 4.19(t, J ═ 6.2Hz, 2H), 4.17-3.99(m, 2H), 3.88(t, J ═ 11.7Hz, 1H), 3.60(d, J ═ 12.9Hz, 1H), 3.27-2.75 (m, 3H), 2.7 (dd, 7H), 1H), 3.5 (d, J ═ 0.7H), 1H, 3.7H, 3.60(d, 3.9, 3.75 (d, J ═ 12.9, 1H), 3.75 (m, 3.7H), 3.7H, 1H), 0.7H, 1H, 0. ESI-MS M/z calculated 649.22943, Experimental 650.43 (M +1) ⁺(ii) a Retention time: 2.12min (LC method B).

Example 42: preparation of (14S) -12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 161)

Step 1: (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxylic acid (10g, 25.66mmol) in tetrahydrofuran (100mL)To a solution of (2) carbonyl diimidazole (4.7g, 27.71mmol) and the mixture is stirred at ambient temperature for 90min, to which mixture is subsequently added a solution containing (4S) -2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (12.0g, 29.09mmol) in tetrahydrofuran (50mL) followed by the addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (11.5mL, 76.90 mmol) and the mixture stirred at ambient temperature for 18 h. The reaction was diluted with water (250mL) and the mixture was slowly acidified with aqueous hydrochloric acid (23mL, 6M, 138.0 mmol.) the mixture was extracted with ethyl acetate (500mL) and the organic phase was separated, the organic phase was washed with 300mL brine, dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was split into 3 aliquots with acetonitrile and subjected to 415 reverse phase C ₁₈Performing column chromatography, and eluting with 50% -100% acetonitrile/water gradient to obtain product (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] as waxy solid]Propoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (13.63g, 68%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.75(s, 1H), 8.39(t, J ═ 2.2Hz, 1H), 8.10(d, J ═ 8.4Hz, 1H), 7.70 (d, J ═ 8.3Hz, 1H), 7.62(dd, J ═ 8.5, 7.2Hz, 1H), 7.24-7.14(M, 2H), 6.74(d, J ═ 8.5 Hz, 1H), 6.20(dd, J ═ 8.6, 2.9Hz, 1H), 4.23(t, J ═ 6.2Hz, 2H), 3.51(dt, J ═ 18.4, 9.2 Hz, 1H), 3.24(s, 2H), 2.74(t, J ═ 10.5Hz, 1H), 2.05-1.96(M, 1.91, 1H), 1.84 (M-0.7H, 1H), 5H, 1H, 5M, 15.83 (M, 15M, 0.5H, 15M, 0.7H, 15M, 15H, 1H.⁺(ii) a Retention time: 2.38min (LC method B).

Step 2: 2-chloro-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] propylamino ] -2-pyridinyl ] sulfonyl ] -6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carboxamide (dihydrochloride)

To (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Propoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]To a solution of tert-butyl (13.5 g, 17.21mmol) 2, 2-dimethyl-pyrrolidine-1-carboxylate in dichloromethane (100mL) and toluene (50mL) was added dioxane containing hydrochloric acid (20mL, 4M, 80.00 mmol). The mixture was stirred at ambient temperature for 16 h.the solvent was removed in vacuo and the residue was further evaporated from 200mL of toluene to give 2-chloro-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] amine]Propylamino group]-2-pyridyl]Sulfonyl radical]-6- [3- [3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxamide (dihydrochloride) (12.7g, 97%) was used without further purification.¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.80(s, 1H), 9.31(s, 1H), 9.14(s, 1H), 8.41(d, J ═ 2.9Hz, 1H), 8.11(d, J ═ 8.3Hz, 1H), 7.72(d, J ═ 8.3Hz, 1H), 7.63(dd, J ═ 8.5, 7.2 Hz, 1H), 7.19-7.15(m, 3H), 6.78(dd, J ═ 8.6, 0.7Hz, 1H), 6.21(d, J ═ 2.9Hz, 1H), 4.24(t, J ═ 6.2Hz, 2H), 3.28(dh, J ═ 27.2, 6.6, 6.1, 3H), 2.82(tq, J ═ 11.8, 7.2 Hz, 2H), 3.28(dh, J ═ 27.2, 6.6, 6.1, 3H), 2.82(tq, 11.8, 7.8, 7, 2H, 1H), 1H), 1.81-1H, 1.68 (d, 1H), 1H, 1. ESI-MS M/z calculated 683.2268, Experimental 684.3(M +1) ⁺(ii) a Retention time: 2.47min (LC method D).

And step 3: (14S) -12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Propoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 161)

To 2-chloro-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] group]Propylamino group]-2-pyridyl]Sulfonyl radical]-6- [3- [3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxamide (dihydrochloride) (12.7g, 16.77mmol) in NMP (200)mL) was added potassium carbonate (11.47g, 82.99 mmol) followed by cesium fluoride (2.75g, 18.10mmol) and the mixture was purged with nitrogen for 5min and heated at 150 ℃ for 22h, then the reaction mixture was cooled to room temperature and added to chilled water (600 mL). The mixture was carefully acidified with aqueous hydrochloric acid (26mL, 6M, 156.0mmol) to give a creamy yellow foamy slurry. The slurry was stirred at ambient temperature for 1 h. The solid was collected by filtration using a medium pore frit buchner funnel. Dilute the wet cake with acetonitrile and perform C₁₈Reverse phase chromatography on silica gel eluting with a gradient of 50% to 100% acetonitrile/water to give an off-white foam which is further dried under vacuum at 45 ℃ for 3 days to give (14S) -12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl ] methane ]Propoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 161) (6.0g, 55%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.48(s, 1H), 8.21(d, J ═ 2.7Hz, 1H), 7.81(d, J ═ 8.2Hz, 1H), 7.57(dd, J ═ 8.5, 7.2Hz, 1H), 7.05(d, J ═ 7.1 Hz, 1H), 6.97(d, J ═ 8.5Hz, 1H), 6.91(d, J ═ 8.2Hz, 1H), 6.71(d, J ═ 8.5Hz, 1H), 6.12(d, J ═ 2.8Hz, 1H), 4.20(t, J ═ 6.2Hz, 2H), 3.92(d, J ═ 12.5Hz, 1H), 3.16(s, 1H), 2.95(d, J ═ 13.3, 2H, 1H, 3.5H), 3.16(s, 1H), 2.95(d, J ═ 1H), 3.7.7.7H, 1H, 7.5H), 7.7.7.7H, 1H, 7H, 1H, 7(d, 7.5H, 1H), 6.7H, 1H, 7(d, 7.5H), 6.7H, 7.5H, 7H, 7.7H, 7H, 1H, 7, 0.76(q, J ═ 3.0, 1.7Hz, 2H). ESI-MS M/z calculated 647.2502, Experimental 648.3(M +1)⁺(ii) a Retention time: 9.64min (LC method F).

Example 43: preparation of 8- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 162) and 8- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17 ].3.1.111，14.05，10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 163)

Step 1: 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl ] -N- [ [6- [2- (5, 5-dimethylpyrrolidin-3-yl) oxyethylamino ] -2-pyridinyl ] sulfonyl ] pyridine-3-carboxamide

In a 50mL flask, 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (400mg, 1.106mmol) and carbonyldiimidazole (270mg, 1.665mmol) were evacuated and backfilled with nitrogen (3 ×). Anhydrous tetrahydrofuran (10mL) was added and the reaction was stirred at 50 ℃ for 90 min. Next, 2-dimethyl-4- [2- [ (6-sulfamoyl-2-pyridyl) amino group was added]Ethoxy radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (158mg, 0.3812mmol) and 1, 8-diazabicyclo [5.4.0]A solution of undec-7-ene (430mg, 2.825mmol) in tetrahydrofuran (4 mL). The reaction was heated at 50 ℃ overnight, diluted with ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, evaporated in vacuo and purified by silica gel chromatography, eluting with a gradient of 0-50% ethyl acetate/hexanes to give the intermediate, which was dissolved in dichloromethane (5mL) and treated with trifluoroacetic acid (1,000 μ L, 12.98mmol) and stirred at room temperature for 2 h. The solvent was removed in vacuo and the residue was quenched with aqueous sodium bicarbonate and ethyl acetate. A white solid precipitate formed. The biphasic mixture was filtered and the solid product was washed with ethyl acetate. The organic extract is separated from the aqueous phase and dried over sodium sulfate, filtered and evaporated in vacuo the solid material from the filter and the evaporation residue are combined and dried in vacuo to give 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl ]-N- [ [6- [2- (5, 5-dimethylpyrrolidin-3-yl) oxyethylamino group]-2-pyridyl]Sulfonyl radical]Pyridine-3-carboxylic acid amidesAmine (310mg, 43%). ESI-MS M/z calculated 657.25, Experimental value 658.32(M +1)⁺(ii) a Retention time: 0.68min (LC method B).

Step 2: 8- [3- (3, 3-Dicyclopropylpropoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 156)

2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl]-N- [ [6- [2- (5, 5-dimethylpyrrolidin-3-yl) oxyethylamino group]-2-pyridyl]Sulfonyl radical]Pyridine-3-carboxamide (320mg, 0.4862mmol), potassium carbonate (340mg, 2.460mmol), cesium fluoride (150mg, 0.9875mmol) and

molecular sieves (300mg) were combined and sealed, and purged with nitrogen. Dimethyl sulfoxide (4mL) was added and the mixture was stirred at 150 ℃ overnight. The mixture was filtered and purified by preparative reverse phase HPLC (C)₁₈): gradient/hydrochloric acid modifier purification of 1-99% acetonitrile in water to give 8- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 156) (92.5mg, 30%). ESI-MS M/z calculated 621.2733, Experimental 622.31(M +1)⁺(ii) a Retention time: 2.26min (LC method B).

And step 3: 8- [3- (3, 3-Dicyclopropylpropoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 162) and 8- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-15-oxa-2. lambda⁶-thia-3, 9, 11, 18,23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 163)

Racemic 8- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl was chromatographed by SFC using ChiralPak AS-H (250 × 10mm, 5 μm particle size) and 40% acetonitrile/methanol (90: 10)/60% carbon dioxide mobile phase (10mL/min over 8.0min) (injection volume 70 μ L, 24mg/mL solution in acetonitrile/methanol (90: 10))]-12, 12-dimethyl-15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 156) (90 mg, 0.145mmol) was subjected to chiral separation to give 8- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl ] as the first enantiomer to be eluted]-12, 12-dimethyl-15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 162) (28.4mg, 19%); ESI-MS M/z calculated 621.2733, Experimental 622.38 (M +1)⁺(ii) a Retention time: 2.26min (LC method B) and 8- [3- (3, 3-Dicyclopropylpropoxy) -1H-pyrazol-1-yl as the second enantiomer to be eluted]-12, 12-dimethyl-15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 163) (enantiomer 2) (35.4mg, 39%);¹h NMR (400MHz, dimethylsulfoxide-d)₆)12.58(s，1H)，8.19(d，J＝2.7Hz，1H)，7.79(d，J＝8.2Hz，1H)，7.62-7.55 (m，1H)，7.11(dd，J＝16.4，5.9Hz，2H)，6.94(d，J＝8.2Hz，1H)，6.70(d，J＝8.5Hz， 1H)，6.10(d，J＝2.7Hz，1H)，4.36(t，J＝6.8Hz，2H)，4.19-4.00(m，2H)，3.88(t，J＝ 11.3Hz，1H)，3.60(d，J＝13.0Hz，1H)，3.22(s，1H)，2.86(d，J＝9.5Hz，1H)，2.07 (dd, J ═ 11.8, 5.9Hz, 1H), 1.89(q, J ═ 6.8Hz, 2H), 1.78(t, J ═ 10.9Hz, 1H), 1.57(d, J ═ 10.0Hz, 6H), 0.68(qt, J ═ 8.4, 5.0Hz, 2H), 0.39(q, J ═ 5.9Hz, 4H), 0.34-0.24 (M, 1H), 0.20(dt, J ═ 10.4, 5.2Hz, 2H), 0.03(dt, J ═ 8.0, 4.0Hz, 2H), ESI-MS M/z calculated 621.2733, experimental value 622.42(M +1) ⁺(ii) a Retention time: 2.25min (LC method B).

Example 44: preparation of 20, 20-dimethyl-4- (3- {3- [1- (trifluoromethyl) cyclopropyl [ ]]Propoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosate 2(7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 1) (compound 165) and 20, 20-dimethyl-4- (3- {3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosate 2(7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 166)

Step 1: 4- [3- [3- [ [ 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] pyrazol-1-yl ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxylic acid (275mg, 0.7056mmol) and carbonyldiimidazole (130mg, 0.8017mmol) were combined in anhydrous tetrahydrofuran (5mL) and stirred at 50 ℃ for 60 min. Followed by the addition of 2, 2-dimethyl-4- [3- (3-sulfamoylpyrazol-1-yl) propyl]Pyrrolidine-1-carboxylic acid tert-butyl ester (206mg, 0.5330mmol) and 1, 8-diazabicyclo [5.4.0 ]A solution of undec-7-ene (200. mu.L, 1.337mmol) in tetrahydrofuran (7mL) the reaction was heated at 50 ℃ for 4 h. The reaction was diluted with ethyl acetate andwash with 1M citric acid solution followed by brine. The organics were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexane to 75% ethyl acetate/hexane to give an off-white solid, i.e., 4- [3- [3- [ [ 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] hexane]Propoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Pyrazol-1-yl]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (226mg, 56%). ESI-MS calculated M/z 757.2636, Experimental 758.32(M +1)⁺(ii) a Retention time: 0.88min (LC method A).

Step 2: 20, 20-dimethyl-4- (3- {3- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Propoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac 2(7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (compound 155)

4- [3- [3- [ [ 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] group]Propoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Pyrazol-1-yl]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (226mg, 0.2981 mmol) was dissolved in dichloromethane (5mL) and to the mixture was added dioxane containing hydrochloric acid (2mL, 4M, 8.000mmol) and stirred at room temperature for 30min

Molecular sieves and dimethylsulfoxide (6mL) were combined in a vial, purged with nitrogen, capped, heated to 140 ℃ and stirred for 16h₁₈Column, 30% to 99% acetonitrile (no modifier)/water (5mM hydrochloric acid) for 30min) to afford 20, 20-dimethyl-4- (3- {3- [1- (trifluoromethyl) cyclopropyl ] characterization]Propoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16 ].2.1.111，14.02，7]White solid of docosate 2(7), 3, 5, 11(22), 12-pentaen-8, 10, 10-trione (compound 155) (96mg, 51%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.69(s, 1H), 8.18(d, J ═ 2.8Hz, 1H), 8.00(d, J ═ 2.3Hz, 1H), 7.71(d, J ═ 8.1Hz, 1H), 7.04-6.80 (m, 2H), 6.10(d, J ═ 2.8Hz, 1H), 4.30-4.05(m, 4H), 2.07(s, 3H), 1.99-1.66(m, 6H), 1.55(s, 3H), 1.47(s, 3H), 1.33(t, J ═ 12.3Hz, 1H), 0.98-0.87(m, 2H), 0.75(s, 2H), 0.64(s, 1H). ESI-MS M/z calculated 621.2345, Experimental 622.24(M +1)⁺(ii) a Retention time: 2.22min (LC method B).

And step 3: 20, 20-dimethyl-4- (3- {3- [1- (trifluoromethyl) cyclopropyl ] methyl ester ]Propoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosate 2(7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 1) (compound 165) and 20, 20-dimethyl-4- (3- {3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosate 2(7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 166)

To racemic 20, 20-dimethyl-4- (3- {3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Dodecan 2(7), 3, 5, 11(22), 12-pentaen-8, 10, 10-trione (compound 155) (88mg, 0.1401mmol) was subjected to chiral SFC chromatography. The following SFC protocol was employed: ChiralPak AS-3 (150X 2.1mm), 3 μm; 35 ℃, mobile phase: 28% acetonitrile: methanol (90: 10), 72% carbon dioxide, flow rate 0.5mL/min the first enantiomer to be eluted was 20, 20-dimethyl-4- (3- {3- [1- (trifluoromethyl) cyclopropyl ] isomer]Propoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7 ]Docosate 2(7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 1) (compound 165) (36mg, 82%). ESI-MS M/z calculated 621.2345, Experimental 622.24(M +1)⁺(ii) a Retention time: 2.21min (LC method B). The second enantiomer to be eluted was 20, 20-dimethyl-4- (3- {3- [1- (trifluoromethyl) cyclopropyl ] isomer]Propoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosate 2(7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 166) (34mg, 77%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.69(s, 1H), 8.18(d, J ═ 2.8Hz, 1H), 8.00(d, J ═ 2.3Hz, 1H), 7.71(d, J ═ 8.1Hz, 1H), 7.04-6.80(m, 2H), 6.10(d, J ═ 2.8Hz, 1H), 4.30-4.05(m, 4H), 2.74-2.63(m, 1H), 2.07(s, 3H), 1.99-1.66(m, 7H), 1.55(s, 3H), 1.47(s, 3H), 1.33(t, J ═ 12.3Hz, 1H), 0.98-0.87(m, 2H), 0.75(s, 2H), 0.64(s, 1H). ESI-MS M/z calculated 621.2345, Experimental 622.35(M +1)⁺(ii) a Retention time: 2.21min (LC method B).

Example 45: preparation of (14S) -12, 12-dimethyl-8- (2-oxo-3- {3- [1- (trifluoromethyl) cyclopropyl ]Propyl } pyrrolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 174) and (14S) -12, 12-dimethyl-8- (2-oxo-3- {3- [1- (trifluoromethyl) cyclopropyl]Propyl } pyrrolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 175)

Step 1: 1- (3-bromopropyl) -1- (trifluoromethyl) cyclopropane

To a stirred solution of triphenylphosphine (655mg, 2.497mmol) in anhydrous dichloromethane (10mL) at-15 ℃ under nitrogen atmosphere a solution of molecular bromine (130 μ L, 2.524mmol) in dichloromethane (2 mL) was added dropwise over 8min, and on completion of the addition (pale yellow solution), the mixture was stirred at-15 ℃ for a further 15 min. The mixture was then cooled to-30 ℃ and 3- [1- (trifluoromethyl) cyclopropyl ] was added dropwise over 5min]A solution of propan-1-ol (500mg, 2.379mmol) and pyridine (202 μ L, 2.498mmol) in dichloromethane (3mL) and, on completion of the addition, the mixture was warmed to-5 ℃ and stirred for 1h then the reaction mixture was poured into pentane (250mL) resulting in a large amount of white precipitate. The suspension was filtered through celite and the filtrate was concentrated by rotary evaporation (250 mbar and 30 ℃ water bath) to give a white solid. To this solid was added pentane and the mixture was briefly sonicated and filtered. The filtrate was concentrated to give a white solid, which was again briefly sonicated with pentane and filtered to give crude 1- (3-bromopropyl) -1- (trifluoromethyl) cyclopropane (500mg, 64%) as a clear oil. ¹H NMR (400MHz, chloroform-d), 3.42(t, J ═ 6.4Hz, 2H), 2.09-1.95 (m, 2H), 1.71(d, J ═ 5.8Hz, 2H), 1.36-1.20(m, 2H), 1.02-0.93(m, 2H), 0.61-0.58(m, 2H). NMR showed a purity of about 70% the product was used in the next step without any further purification.

Step 2: 1-benzyl-3- [3- [1- (trifluoromethyl) cyclopropyl ] propyl ] pyrrolidin-2-one

A 100mL three-necked flask was vacuum dried with a heat gun and filled with nitrogen. The flask was charged with 1-benzylpyrrolidin-2-one (0.21mL, 1.312mmol) and anhydrous tetrahydrofuran (2 mL). After cooling to-78 ℃, an n-butyllithium solution (0.59mL, 2.5M, 1.475mmol) (2.5M in hexanes) was added dropwise to allow a pink solution to form after stirring for 20min at-78 ℃ (solution became light yellow), 1- (3-bromopropyl) -1- (trifluoromethyl) cyclo-methyl was added dropwiseA solution of propane (500mg, 1.515mmol) in tetrahydrofuran (0.5mL) (color turned darker yellow) the mixture was stirred in a cooling bath and allowed to slowly warm to room temperature. After 14h, the mixture was quenched by addition of saturated aqueous ammonium chloride solution (50 mL). The product was extracted with ethyl acetate (2X 30mL), the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure, and the crude product was purified by silica gel chromatography using a gradient of ethyl acetate/hexane (0 to 100% over 30min) to give 1-benzyl-3- [3- [1- (trifluoromethyl) cyclopropyl ] as a colorless oil ]Propyl radical]Pyrrolidin-2-one (227mg, 53%).¹H NMR (400MHz, chloroform-d) 7.37 to 7.16(m, 5H), 4.49(d, J ═ 14.7Hz, 1H), 4.41(d, J ═ 14.7Hz, 1H), 3.22 to 3.14(m, 2H), 2.45(qd, J ═ 8.9, 4.3Hz, 1H), 2.23 to 2.10(m, 1H), 1.94 to 1.80(m, 1H), 1.72 to 1.32(m, 6H), 0.99 to 0.88(m, 2H), 0.61 to 0.51(m, 2H). ESI-MS M/z calculated 325.16534, Experimental 326.3(M +1)⁺(ii) a Retention time: 1.9min (LC method B).

And step 3: 3- [3- [1- (trifluoromethyl) cyclopropyl ] propyl ] pyrrolidin-2-one

A100 mL flask was charged with 1-benzyl-3- [3- [1- (trifluoromethyl) cyclopropyl ] under nitrogen]Propyl radical]Pyrrolidin-2-one (227mg, 0.6977mmol), propylamine (3mL), and 1, 2-ethylenediamine (0.3mL, 4.488 mmol). The mixture was cooled to-20 ℃ (external cooling bath temperature) and lithium (47mg, 6.771mmol) was added (line, roughly rinsed with hexane, then freshly cut into smaller pieces). The blue color appeared around the smaller lithium fragments and then rapidly disappeared in a cyclic manner. After 20min at-20 ℃ the blue color became persistent. The reaction was quenched by the addition of methanol (400 μ L) and water (10mL) at-10 ℃. The product was extracted with ethyl acetate (2 × 25 mL.) the combined organic extracts were dried over sodium sulfate and the solvent was evaporated to give the crude material, which was purified by flash chromatography on silica gel using a gradient of methanol/dichloromethane (0% to 15% over 30min) to give 192mg of crude material, which was dissolved in ethyl acetate (30mL) and the organic phase was washed with 0.1N hydrochloric acid (2X 20ml) and 1N hydrochloric acid (2X 20 ml.) the organic phase is then dried over sodium sulfate, filtered and the solvent evaporated to give 3- [3- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Propyl radical]Pyrrolidin-2-one (108mg, 66%).¹H NMR (400MHz, chloroform-d) 5.76 (width s, 1H), 3.41-3.28(m, 2H), 2.40-2.23(m, 2H), 1.88-1.73 (m, 2H), 1.67-1.44(m, 4H), 1.42-1.30(m, 1H), 0.97-0.90(m, 2H), 0.61-0.47 (m, 2H).

ESI-MS M/z calculated 235.1184, Experimental 236.2(M +1)⁺(ii) a Retention time: 1.43min (LC method B).

And 4, step 4: (14S) -12, 12-dimethyl-8- (2-oxo-3- (3- [1- (trifluoromethyl) cyclopropyl)]Propyl } pyrrolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 174) and (14S) -12, 12-dimethyl-8- (2-oxo-3- {3- [1- (trifluoromethyl) cyclopropyl]Propyl } pyrrolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 175)

A4 mL vial was charged with (14S) -8-chloro-12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (100mg, 0.2222 mmol), 3- [3- [1- (trifluoromethyl) cyclopropyl]Propyl radical]Pyrrolidin-2-one (54mg, 0.2295mmol), Pd₂(dba)₃(33mg, 0.03604mmol), Xantphos (21mg, 0.03629mmol), cesium carbonate (430 mg, 1.320mmol) and anhydrous dioxane (1.5 mL.) the mixture was aerated with nitrogen for about 5min (to gel), capped and stirred at 120 ℃ for 14h15min) and hydrochloric acid (4X 950. mu.L injection, 400. mu.L) as modifier were subjected to reverse phase preparative HPLC (C)₁₈) The pure fractions were collected and the organic solvent was evaporated. The resulting aqueous solution was extracted with dichloromethane and the organic phase was dried over sodium sulfate. Filtration followed by evaporation of the filtrate solvent yielded 74mg of a solid. The product was then further purified by flash chromatography on silica gel using a gradient of methanol/dichloromethane (0% to 5% over 30min) to give a mixture of diastereomers, which was subjected to chiral SFC separation (ChiralCel OJ-H (250X 10 mm), 5. mu.M column; mobile phase 22% acetonitrile/methanol (90: 10, no modifier), 78% carbon dioxide, 10 mL/min; concentration 24mg/mL in acetonitrile/methanol/dimethyl sulfoxide (85: 9: 6; injection volume 70. mu.L, 100 bar.) the first diastereomer to be eluted was (14S) -12, 12-dimethyl-8- (2-oxo-3- {3- [1- (trifluoromethyl) cyclopropyl ] sulfoxide ]Propyl } pyrrolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 174) (12.4mg, 17%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.39(s, 1H), 7.67(d, J ═ 8.4Hz, 1H), 7.56(t, J ═ 7.9Hz, 1H), 7.51(d, J ═ 8.5Hz, 1H), 7.04(d, J ═ 7.1Hz, 1H), 6.96 (wide d, J ═ 5.3Hz, 1H), 6.70(d, J ═ 8.5Hz, 1H), 4.04(t, J ═ 9.1Hz, 1H), 3.91 (brq, J ═ 12.6Hz, 1H), 3.80-3.67(M, 1H), 3.11(bt s, 1H), 2.94 (brd, J ═ 13.3Hz, 1H), 2.77-2.57(M, 2H), 2.31-2.31 (19, 1H), 2.83 (19, 1H), 2.84 (ESI, 1H), 2.83-19 (M, 15, 3.⁺(ii) a Retention time: 2.14min (LC method B). The second diastereomer to elute was (14S) -12, 12-dimethyl-8- (2-oxo-3- {3- [1- (trifluoromethyl) cyclopropyl]Propyl } pyrrolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 175) (12.2mg, 17%). ¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.39(s，1H)，7.68(d，J＝8.5Hz, 1H), 7.63-7.48(m, 2H), 7.04(d, J ═ 7.1Hz, 1H), 6.95(br d, J ═ 5.1Hz, 1H), 6.70(d, J ═ 8.5Hz, 1H), 4.04-3.87(m, 2H), 3.82(q, J ═ 9.9, 9.0Hz, 1H), 3.09 (width s, 1H), 2.94(d, J ═ 13.4Hz, 1H), 2.75-2.61(m, 2H), 2.24(q, J ═ 8.7, 7.9Hz, 1H), 2.17-1.96(br m, 1H), 1.87-1.64(m, 4H), 1.64-1.41(m, 12H), 1.41-1.92 (m, 1.84H), 0.84-0 (m, 0H), 71H). ESI-MS M/z calculated 648.27057, Experimental 649.4(M +1)⁺(ii) a Retention time: 2.12min (LC method B).

Example 46: preparation of 4- [3- (2- { dispiro [2.0.2.1]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-20, 20-dimethyl-10. lambda.⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac 2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (compound 176)

Step 1: 7- (bromomethyl) dispiro [2.0.2.1] heptane

A1000 mL 3-neck round bottom flask was equipped with a mechanical stirrer, cooling bath, addition funnel, J-Kem temperature probe, and nitrogen inlet/outlet. The vessel was charged with triphenylphosphine (102.7mL, 443.2 mmol) and dichloromethane (1L) under a nitrogen atmosphere to provide a clear colorless solution. Dry ice was added portion by portion to the cooling bath until a pot temperature of-15 ℃ was obtained. The addition funnel was charged with a solution of bromine (22.82mL, 443.0mmol) in dichloromethane (220mL, 10mL/g), which was then added dropwise over 1h dry ice was added portionwise to the cooling bath, maintaining the pot temperature at-15 ℃ during the addition. After completion of the bromine addition, the pale yellow suspension was stirred for a further 15min at-15 ℃ at which time the suspension was cooled to-30 ℃ and the addition funnel was charged with dispiro [2.0.2.1] ]Hept-7-ylmethanol (50g, 402.6mmol), pyridine (35.82 mL, 4)42.9mmol) and dichloromethane (250mL, 5 mL/g). The clear pale yellow solution was then added dropwise over 1.5h, maintaining the pot temperature at-30 ℃. The resulting clear pale yellow reaction mixture was gradually warmed to a pot temperature of-5 ℃ and then stirred at-5 ℃ for 1 h. The reaction mixture was then poured into hexane (2000mL) such that a precipitate formed, the suspension was stirred at room temperature for 30min and then filtered through a frit Buchner funnel with 20mm celite bed, the clarified filtrate (water bath temperature at 20 ℃) was concentrated under reduced pressure to provide a yellow oil that was present with some precipitate, the oil was diluted with some hexane, allowed to stand at room temperature for 15min, and then filtered through a frit Buchner funnel with 20mm celite bed, the clarified filtrate (water bath temperature at 20 ℃) was concentrated under reduced pressure to provide 7- (bromomethyl) dispiro [2.0.2.1 ] as a clear yellow oil]Heptane (70g, 93%).¹H NMR (400MHz, chloroform-d) 3.49(d, J ═ 7.5Hz, 2H), 1.90(t, J ═ 7.5Hz, 1H), 1.06-0.84(m, 4H), 0.71(ddd, J ═ 9.1, 5.1, 4.0Hz, 2H), 0.54 (dddd, J ═ 8.6, 4.8, 3.8, 1.0Hz, 2H).

Step 2: 2-dispiro [2.0.2.1] hept-7-ylacetonitrile

A1000 mL 3-neck round bottom flask was equipped with a mechanical stirrer, a cooling bath as an auxiliary containment, a J-Kem temperature probe, and a nitrogen inlet/outlet into the vessel was charged 7- (bromomethyl) dispiro [2.0.2.1] under a nitrogen atmosphere]Heptane (35g, 187.1mmol) and dimethyl sulfoxide (245mL) to provide a clear amber solution. Stirring was started and the pot temperature was recorded as 19 ℃ the vessel was then charged with sodium cyanide (11.46g, 233.8mmol) which was added all at once as a solid, giving a dark colored solution and allowing gradual exotherm to 49 ℃ over 15min after a few minutes, the pot temperature started to decrease and the mixture was continued to be stirred overnight at room temperature (about 15h). the dark colored reaction mixture was quenched with ice cold saturated sodium carbonate solution (500mL) and then transferred to a separatory funnel and partitioned with diethyl ether (500 mL). The organics were removed and the residual aqueous solution was extracted with diethyl ether (2X 250mL)The combined organics were washed with water (500mL), dried over sodium sulfate (200g) and then filtered through a frit buchner funnel. The clear amber filtrate was concentrated under reduced pressure (bath temperature 20 ℃) to provide 2-dispiro [2.0.2.1] as a clear dark amber oil]Hept-7-ylacetonitrile (21g, 84%). ¹H NMR (400MHz, chloroform-d) 2.42(d, J ═ 6.6Hz, 2H), 1.69(t, J ═ 6.6Hz, 1H), 1.02-0.88(m, 4H), 0.79-0.70(m, 2H), 0.66-0.55 (m, 2H).

And step 3: 2-dispiro [2.0.2.1] hept-7-ylacetic acid

To 2-dispiro [2.0.2.1]]To a solution of hept-7-ylacetonitrile (2.1g, 14.19mmol) in EtOH (32mL) was added sodium hydroxide (5.12g, 128.0mmol) followed by water (13mL) and the resulting solution was stirred and heated to 70 ℃ overnight then the mixture was cooled to room temperature, diluted with water and extracted with diethyl ether. The aqueous phase was adjusted to pH 1 by addition of 6N hydrochloric acid (resulting in a cloudy precipitate) and extracted with diethyl ether (3 ×). the organic phase was dried (magnesium sulfate), filtered and concentrated to give 2-dispiro [2.0.2.1] as an orange solid]Hept-7-ylacetic acid (2.19g, 99% yield, 98% purity) was used in the next step without further purification.¹H NMR (400MHz, chloroform-d) 2.44(d, J ═ 6.9Hz, 2H), 1.67(t, J ═ 6.9Hz, 1H), 0.91 (ddd, J ═ 9.0, 5.2, 3.9Hz, 2H), 0.81(dddd, J ═ 8.9, 5.2, 3.9, 0.5Hz, 2H), 0.69(ddd, J ═ 8.9, 5.2, 3.9Hz, 2H), 0.56-0.44(m, 2H).

And 4, step 4: 2-dispiro [2.0.2.1] hept-7-ylethanol

To lithium aluminum hydride (827.4mg, 902.3. mu.L, 21.80mmol) dissolved in tetrahydrofuran (33.71mL) cooled in an ice/water bath was added dropwise over 15min a solution containing 2-dispiro [2.0.2.1] ]Hept-7-ylacetic acid (2.552 g, 16.77mmol) in tetrahydrofuran (7.470mL) was maintainedThe reaction temperature is less than 20 ℃. The mixture was stirred for a total of 18 h, allowing it to gradually warm to ambient temperature. The mixture was cooled with an ice/water bath and quenched sequentially by slow addition of water (838.4mg, 838.4 μ L, 46.54mmol), followed by sodium hydroxide (1.006mL, 5M, 5.031 mmol), followed by water (2.493g, 2.493mL, 138.4mmol) to give a white granular slurry which was filtered through celite. The filtrate was concentrated in vacuo at about 300 mbar and 30 ℃ water bath. The residue was diluted with diethyl ether, dried (magnesium sulfate), filtered and concentrated in vacuo in a water bath at about 300 mbar and 30 ℃ followed by vacuum concentration for about 30 seconds to give 2-dispiro [2.0.2.1]]Hept-7-ylethanol (2.318g, 100%) was used directly in the subsequent step without further purification.¹H NMR (400 MHz, chloroform-d) 3.64(s, 2H), 1.68(d, J ═ 6.7Hz, 2H), 1.39(s, 1H), 1.31(s, 1H), 0.82 (d, J ═ 14.0Hz, 4H), 0.65(s, 2H), 0.50(d, J ═ 3.6Hz, 2H).

And 5: 3- (2-Dispiro [2.0.2.1] hept-7-ylethoxy) pyrazole-1-carboxylic acid tert-butyl ester

To 5-oxo-1H-pyrazole-2-carboxylic acid tert-butyl ester (2.942g, 15.97mmol) and 2-dispiro [2.0.2.1 ]To a solution of hept-7-ylethanol (2.318g, 16.77mmol) in tetrahydrofuran (36.78mL) was added triphenylphosphine (4.399g, 16.77mmol), diisopropyl azodicarboxylate (3.391g, 3.302mL, 16.77mmol) was added slowly dropwise to the mixture over 10min (a slight exotherm was noted). The reaction mixture was stirred at room temperature for 30min, then at 50 ℃ for 30min, tetrahydrofuran was removed in vacuo, toluene (23.54mL) was added to the crude residue, and the mixture was stirred overnight as the precipitate gradually crystallized]Hept-7-ylethoxy) pyrazole-1-carboxylic acid tert-butyl ester (3.449g, 71%). ESI-MS m/zCalculations 304.17868, Experimental 305.1(M +1)⁺(ii) a Retention time: 0.82min (LC method A).

Step 6: 3- (2-dispiro [2.0.2.1] hept-7-ylethoxy) -1H-pyrazole

Mixing 3- (2-dispiro [2.0.2.1]]Hept-7-ylethoxy) pyrazole-1-carboxylic acid tert-butyl ester (5.304g, 17.43mmol) was dissolved in dichloromethane (53.04mL) and trifluoroacetic acid (29.81g, 20.14mL, 261.4mmol) and the reaction stirred at room temperature for 120min ]Hept-7-ylethoxy) -1H-pyrazole (3.56g, 100%). ESI-MS M/z calculated 204.12627, Experimental 205.1(M +1)⁺(ii) a Retention time: 0.59min (LC method A).

And 7: 2-chloro-6- [3- (2-dispiro [2.0.2.1] hept-7-ylethoxy) pyrazol-1-yl ] pyridine-3-carboxylic acid tert-butyl ester

2, 6-dichloropyridine-3-carboxylic acid tert-butyl ester (4.322g, 17.42mmol), 3- (2-dispiro [2.0.2.1]]Hept-7-ylethoxy) -1H-pyrazole (3.559g, 17.42mmol) and potassium carbonate (2.891g, 20.92mmol) were combined in anhydrous dimethylsulfoxide (71.18 mL). Addition of 1, 4-diazabicyclo [2.2.2]Octane (391.1mg, 3.487 mmol) and the mixture stirred at room temperature under nitrogen for 16h the reaction mixture was diluted with water (136.9mL) and stirred for 15min, the resulting white solid was filtered and washed with water, the solid was dissolved in dichloromethane and dried over magnesium sulfate, the mixture was filtered and evaporated to give 2-chloro-6- [3- (2-dispiro [2.0.2.1] as a white solid]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (5.69g, 79%).¹H NMR (400MHz, chloroform-d) 8.35(d, J ═ 2.9Hz, 1H), 8.18(d, J ═ 8.4Hz, 1H), 7.69(d, J ═ 8.4Hz, 1H), 5.94(d, J ═ 2.9Hz, 1H), 4.25(s, 2H), 1.90(d, J ═ 6.8Hz, 2H), 1.62(s, 9H), 1.49(t, J ═ 6.6Hz, 1H), 0.85(d, J ═ 1.5Hz, 4H), 0.65(d, J ═ 1.5Hz, 2H), 0.52(d, J ═ 1.1Hz, 2H). ESI-MS calculated M/z 415.16626, Experimental 360.0(M-tBu) ⁺(ii) a Retention time: 2.09min (LC method B).

And 8: 2-chloro-6- [3- (2-dispiro [2.0.2.1] hept-7-ylethoxy) pyrazol-1-yl ] pyridine-3-carboxylic acid

2-chloro-6- [3- (2-dispiro [2.0.2.1]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (5.85g, 14.07mmol) was dissolved in dichloromethane (58.5mL) and trifluoroacetic acid (16.26mL, 211.1mmol) and the reaction was stirred at room temperature for 16 h. The reaction was evaporated, and ether was added to the resulting solid, and then the ether was removed under reduced pressure. This evaporation from the ether was repeated two more times to yield a white solid, 2-chloro-6- [3- (2-dispiro [2.0.2.1]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (5.06g, 100%).¹H NMR (400 MHz, chloroform-d) 8.41(d, J ═ 8.5Hz, 1H), 8.37(d, J ═ 2.9Hz, 1H), 7.75(d, J ═ 8.5Hz, 1H), 5.97(d, J ═ 2.9Hz, 1H), 4.27(s, 2H), 1.91(d, J ═ 6.7Hz, 2H), 1.50(s, 1H), 0.85 (d, J ═ 1.5Hz, 4H), 0.71-0.62(m, 2H), 0.52(d, J ═ 1.1Hz, 2H). ESI-MS M/z calculated 359.10367, Experimental 360.2(M +1)⁺(ii) a Retention time: 2.16min (LC method B).

And step 9: 4- [3- [3- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1] hept-7-ylethoxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] pyrazol-1-yl ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- (2-dispiro [2.0.2.1 ]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (400mg, 1.112mmol) and carbonyldiimidazole (273.5mg, 1.687mmol) were combined in tetrahydrofuran (2mL) and stirred at room temperature for 90min, then 2, 2-dimethyl-4- [3- (3-sulfamoylpyrazol-1-yl) propyl ] was added]Pyrrolidine-1-carboxylic acid tert-butyl ester (429.5mg, 1.111mmol) followed by addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (430.8mg, 2.830mmol) and the reaction stirred at room temperature for 1h, then heated to 50 ℃ and stirred overnight, the reaction was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate, followed by brine the organics were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexane to 100% ethyl acetate to give 4- [3- [3- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1 ] as an off-white solid]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Pyrazol-1-yl]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (350mg, 43%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)8.34(s, 1H), 8.08(d, J ═ 8.2Hz, 1H), 7.77(s, 1H), 7.62(d, J ═ 8.3Hz, 1H), 6.71-6.49(M, 1H), 6.10(d, J ═ 2.8Hz, 1H), 4.23(s, 2H), 4.13(s, 2H), 3.52(s, 1H), 2.73(d, J ═ 6.0Hz, 1H), 2.08(d, J ═ 6.7Hz, 1H), 1.81(q, J ═ 6.6Hz, 5H), 1.47(t, J ═ 6.5Hz, 1H), 1.40-1.21(M, 18H), 0.83(d, J ═ 2.0, 4H), 0.66 (M, 60, 60.84, 0.84, 0.85m, 18H), 0.83 (M, 18H), 2.84, 18H, M ⁺(ii) a Retention time: 0.92min (LC method A).

Step 10: 2-chloro-N- [1- [3- (5, 5-dimethylpyrrolidin-3-yl) propyl ] pyrazol-3-yl ] sulfonyl-6- [3- (2-dispiro [2.0.2.1] hept-7-ylethoxy) pyrazol-1-yl ] pyridine-3-carboxamide

Reacting 4- [3- [3- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Pyrazol-1-yl]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (350mg, 0.4806 mmol) was dissolved in dichloromethane (1.527mL), and trifluoroacetic acid (2.192g, 1.481mL, 19.22mmol) was added to the mixture, and the resulting mixture was stirred at room temperature for 60 min. The mixture was concentrated to dryness under reduced pressure, dissolved in a saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate containing a small amount of methanol for easy dissolution and the layers were separated by rotary evaporation, followed by concentration of the organic layer by a high vacuum pump to give 2-chloro-N- [1- [3- (5, 5-dimethylpyrrolidin-3-yl) propyl ] as an off-white solid]Pyrazol-3-yl]Sulfonyl-6- [3- (2-dispiro [2.0.2.1]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carboxamide (301.9mg, 100%).¹H NMR(400MHz， CDCl₃)8.28(d，J＝2.8Hz，1H)，8.21(d，J＝8.3Hz，1H)，7.61(d，J＝8.3Hz，1H)， 7.44(s，1H)，6.67(s，1H)，5.88(d，J＝2.8Hz，1H)，4.22(t，J＝6.8Hz，2H)，4.17(s， 2H)，3.55(s，1H)，3.03(s，1H)，2.23(s，1H)，1.88(d，J＝6.7Hz，2H)，1.83(s，3H)， 1.48(s，1H)，1.46-1.35(m，5H)，1.35-1.24(m，4H)，0.84(t，J＝1.9Hz，4H)，0.63(d， J＝1.6Hz，2H)，0.51(d，J＝1.1Hz，2H).

Step 11: 4- [3- (2- { dispiro [2.0.2.1]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-20, 20-dimethyl-10. lambda. ⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac 2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (compound 176)

2-chloro-N- [1- [3- (5, 5-dimethylpyrrolidin-3-yl) propyl group]Pyrazol-3-yl]Sulfonyl-6- [3- (2-dispiro [2.0.2.1 ]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carboxamide (310mg, 0.4935mmol), potassium carbonate (341.1mg, 2.468mmol), cesium fluoride (112.8mg, 0.7426mmol),

Molecular sieves and dimethylsulfoxide (9.3mL) were combined in a vial, purged with nitrogen, capped, heated to 155 ℃ and stirred for 20h, cooled to room temperature, then the mixture was filtered, diluted with ethyl acetate and carbonatedThe sodium bicarbonate solution was washed with saturated aqueous solution, followed by brine. The organics were separated, dried over sodium sulfate, evaporated, and then purified by silica gel chromatography using a gradient of 100% hexane to 100% ethyl acetate to give 4- [3- (2- { dispiro [2.0.2.1 ] as a white solid]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-20, 20-dimethyl-10. lambda.⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac 2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (compound 176) (117mg, 40%). ¹H NMR(400MHz，CDCl₃)8.37(s, 1H), 8.16(d, J ═ 2.8Hz, 1H), 7.68(d, J ═ 8.3Hz, 1H), 7.48(d, J ═ 2.3Hz, 1H), 7.26(s, 1H), 7.07(d, J ═ 2.3Hz, 1H), 7.02(d, J ═ 8.3Hz, 1H), 5.86(d, J ═ 2.8Hz, 1H), 4.36(d, J ═ 13.5Hz, 1H), 4.24 (s, 2H), 3.95(d, J ═ 12.4Hz, 1H), 2.74(t, J ═ 8.1Hz, 1H), 2.15(d, J ═ 4.2Hz, 2H), 2.08-1.93(m, 3.93 (m, 1H), 89(d, 1.6H, 1H), 7.5H, 7.5 (d, 1H, 5H), 3.5H, 1H, 5(d, 3.5H), 3.5H, 1H, 5H, 1H, 7.5H, 1H, 5H, 1H, and 1H. ESI-MS M/z calculated 591.26276, Experimental 592.4(M +1)⁺(ii) a Retention time: 2.37min (LC method B).

Example 47: preparation of (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethyl) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 177) and (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethyl) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 178)

Step 1: 7- (2-bromoethyl) dispiro [2.0.2.1] heptane

To a stirred solution of triphenylphosphine (1.07g, 4.080mmol) in anhydrous dichloromethane (15mL) was added dropwise a solution of molecular bromine (0.22mL, 4.271mmol) in dichloromethane (3 mL) at-15 ℃ over 10min under nitrogen atmosphere, and on completion of the addition (light orange solution), the mixture was stirred at-15 ℃ for a further 15 min. The mixture was then cooled to-30 ℃ and 2-dispiro [2.0.2.1] was added dropwise over 5min]A solution of hept-7-ylethanol (537 mg, 3.885mmol) and pyridine (330. mu.L, 4.080mmol) in dichloromethane (4mL) and on completion of the addition the mixture was warmed to-5 ℃ and stirred for 2h, then the reaction mixture was poured into pentane (350 mL) yielding a large amount of yellow precipitate, this suspension was filtered and the filtrate was concentrated by rotary evaporation (250 mbar and 30 ℃ water bath) to give a white solid. Pentane was added to the solid and the mixture was briefly sonicated and filtered concentrating the filtrate to give 7- (2-bromoethyl) dispiro [2.0.2.1] as a pale yellow oil]Heptane (634mg, 81%) which was used in the next step without any further purification. ¹H NMR (400 MHz, chloroform-d) 3.37(t, J ═ 7.1Hz, 2H), 2.02-1.96(m, 2H), 1.46(t, J ═ 6.4Hz, 1H), 0.91-0.78(m, 4H), 0.66(ddd, J ═ 8.1, 4.8, 3.6Hz, 2H), 0.50(dddd, J ═ 9.0, 4.9, 3.7, 0.9Hz, 2H).

Step 2: 1-benzyl-3- (2-dispiro [2.0.2.1] hept-7-ylethyl) pyrrolidin-2-one

A 100mL three-necked flask was vacuum dried with a heat gun and filled with nitrogen. The flask was charged with 1-benzylpyrrolidin-2-one (0.46mL, 2.875mmol) and anhydrous tetrahydrofuran (5mL) and after cooling to-78 deg.C, an n-butyllithium solution (1.3mL, 2.5M, 3.250mmol) (2.5M in hexanes) was added dropwise such that an orange solution formed. Stirring at-78 deg.C for 20min, and adding 7- (2-bromoethyl) dispiro [2.0.2.1] dropwise]Heptane (611 mg,3.038mmol) in tetrahydrofuran (1mL) after stirring the mixture in a cooling bath, slowly warming to room temperature, 17h, the mixture was quenched by addition of saturated aqueous ammonium chloride (50mL), the product was extracted with ethyl acetate (2 x 30mL), the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of ethyl acetate/hexane (0 to 100% over 30 min). Evaporation of the solvent gave 1-benzyl-3- (2-dispiro [2.0.2.1] as a colorless oil ]Hept-7-ylethyl) pyrrolidin-2-one (352mg, 41%).¹H NMR (400MHz, chloroform-d) 7.38-7.17(m, 5H), 4.45(q, J ═ 14.7Hz, 2H), 3.22-3.10(m, 2H), 2.42(qd, J ═ 8.8, 4.1Hz, 1H), 2.21-2.07(m, 1H), 2.00-1.85(m, 1H), 1.62(dq, J ═ 12.7, 8.4Hz, 1H), 1.51-1.42(m, 2H), 1.42-1.25 (m, 2H), 0.88-0.71(m, 4H), 0.68-0.55(m, 2H), 0.51-0.39(m, 2H). ESI-MS M/z calculated 295.1936, Experimental 296.3(M +1)⁺(ii) a Retention time: 2.08min (LC method B).

And step 3: 3- (2-dispiro [2.0.2.1] hept-7-ylethyl) pyrrolidin-2-one

A100 mL flask was charged with 1-benzyl-3- (2-dispiro [2.0.2.1] under nitrogen]Hept-7-ylethyl) pyrrolidin-2-one (350mg, 1.185mmol), propylamine (4mL) and 1, 2-ethylenediamine (510 μ L, 7.629mmol) the mixture was cooled to-20 ℃ (external cooling bath temperature) and lithium (72mg, 10.37mmol) was added (line, roughly rinsed with hexane, then freshly cut into small pieces). The blue color appeared around the small lithium fragments and then disappeared rapidly after 2h at-20 ℃ the blue color became persistent. The reaction was quenched by the addition of methanol (400 μ L) and water (40 mL) at-20 ℃. After warming to room temperature, the white solid in the suspension was filtered, washed with water and air-dried approximately (200 mg). This material was purified by flash chromatography on silica gel using a gradient of methanol/dichloromethane (0 to 15% over 30min) to give 3- (2-dispiro [2.0.2.1] as a white solid ]Hept-7-ylethyl) pyrrolidin-2-one (173 mg, 71%).¹H NMR (400MHz, chloroform-d) 5.69 (width s, 1H), 3.41-3.24(m, 2H), 2.37-2.20 (m, 2H), 1.88(dddd, J ═ 13.4, 9.1, 7.4, 3.8Hz, 1H), 1.83-1.67(m, 1H), 1.53-1.41 (m, 2H), 1.41-1.29(m, 2H), 0.86-0.74(m, 4H), 0.67-0.59(m, 2H), 0.51-0.39 (m, 2H). ESI-MS M/z calculated 205.14667, Experimental 206.2(M +1)⁺(ii) a Retention time: 1.61min (LC method B).

And 4, step 4: (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethyl) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 177) and (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethyl) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 178)

A4 mL vial was charged with (14S) -8-chloro-12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (100mg, 0.2222 mmol), 3- (2-dispiro [2.0.2.1 ]]Hept-7-ylethyl) pyrrolidin-2-one (47mg, 0.2289mmol), Pd₂(dba)₃(32mg, 0.03495mmol), xanthphos (19mg, 0.03284mmol), cesium carbonate (365mg, 1.120 mmol) and anhydrous dioxane (1.5 mL). The mixture was sparged with nitrogen for about 5min, capped and stirred at 120 ℃ for 16 h. The organic solvent was evaporated by blowing nitrogen into the vial. The reaction was diluted with dimethyl sulfoxide (3mL), microfiltered, and subjected to reverse phase preparative HPLC (C) using a gradient of acetonitrile in water (1 to 99% over 15min) and hydrochloric acid as a modifier₁₈) The pure fractions were collected and the organic solvent was evaporated, the resulting aqueous solution was extracted with dichloromethane and the organic phase was dried over sodium sulfate. Evaporating the solvent to obtain a residueThe residue was purified by flash chromatography on silica gel using a gradient of methanol/dichloromethane (0 to 5% over 30 min). The resulting product was dissolved in dimethyl sulfoxide (2mL) and further purified by preparative HPLC using a 50-99% acetonitrile/water gradient (hydrochloric acid as modifier) over 15 min. The pure fractions were collected and the organic solvent was evaporated, the resulting aqueous solution was extracted with dichloromethane and the organic phase was dried over sodium sulfate. Evaporation of the solvent gave a diastereoisomeric mixture which was subjected to SFC separation (ChiralCel OJ-H (250X 10mm), 5. mu.M column; mobile phase 24% acetonitrile/methanol (90: 10, without modifier), 76% carbon dioxide, 10 mL/min; concentration 24mg/mL in acetonitrile/methanol/dimethylsulfoxide (72: 8: 20; injection volume 70. mu.L, 100 bar.) the pure product fractions were combined and the solvent evaporated and the residue triturated in dichloromethane/hexane the first diastereomer to be eluted was (14S) -8- [3- (2- { dispiro [2.0.24.13 ] ]Hept-7-yl } ethyl) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 177) (6.3mg, 9%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.38(s, 1H), 7.67(d, J ═ 8.5Hz, 1H), 7.62 to 7.45(m, 2H), 7.03(d, J ═ 7.2Hz, 1H), 6.95 (width s, 1H), 6.70(d, J ═ 8.7Hz, 1H), 4.04 (t, J ═ 8.9Hz, 1H), 3.91(br dd, J ═ 25.4, 13.2Hz, 1H), 3.74(q, J ═ 9.0, 8.4Hz, 1H), 3.11(br s, 1H), 2.94(br d, J ═ 13.5Hz, 1H), 2.76 to 2.63(m, 1H), 2.64 to 2.54(m, 1H), 2.22(q, J ═ 9.8, 8.92, 1H), 1H, 2.63(m, 9, 8.5Hz, 1H), 1H, 2.63 (q, 9, 8.68, 8, 8.8, 1H, experimental value 619.5(M +1)⁺(ii) a Retention time: 2.37min (LC method B.) the second diastereomer to be eluted is (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethyl) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 17)8)(5.2mg， 7％).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.38(s, 1H), 7.67(d, J ═ 8.5Hz, 1H), 7.62-7.45 (M, 2H), 7.03(d, J ═ 7.0Hz, 1H), 6.95 (width s, 1H), 6.70(d, J ═ 8.6Hz, 1H), 3.93 (t, J ═ 9.3Hz, 2H), 3.82(q, J ═ 9.9, 8.9Hz, 1H), 3.10(br s, 1H), 2.93(br d, J ═ 13.0 Hz, 1H), 2.76-2.55(M, 2H), 2.31-2.17(M, 1H), 2.09(br s, 1H), 1.86-1.63(M, 4H), 1.61-1.29(M, 0.86H), 0.14-0.17 (M, 1H), experimental values (M, 0.619H, 5M, 5H), MS, 25M, 5-2H, 5M, 5H, 5M, 1H, and calculated values of⁺(ii) a Retention time: 2.37min (LC method B).

Example 48: preparation of (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 179) and (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 180)

Step 1: 3- (2-dispiro [2.0.2.1] hept-7-ylethoxy) pyrrolidin-2-one

A100 mL flask was charged with 2-dispiro [2.0.2.1] under nitrogen]Hept-7-ylethanol (502mg, 65% w/w, 2.361mmol) (containing 35% w/w residual tetrahydrofuran), 3-bromopyrrolidin-2-one (390 mg, 2.378mmol) and anhydrous tetrahydrofuran (12 mL.) the mixture was cooled to-50 ℃ followed by dropwise addition of [ bis (trimethylsilyl) amino]Potassium (10mL, 0.5M in toluene)5.000mmol) and the mixture was stirred at-50 ℃ for 15-20min, followed by stirring in an ice bath at 0 ℃ for 3 h. After allowing the reaction to warm slowly to room temperature (micro-powder reaction mixture) 14h, the mixture was cooled to 0 ℃, then glacial acetic acid (210 μ L, 3.693mmol) was added to the reaction, giving an orange slurry, brine (75mL) and ethyl acetate (75mL) were added and the two phases separated, the aqueous phase was further extracted with ethyl acetate (2 × 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and the solvent evaporated the crude residue was purified by silica gel chromatography (0-15% methanol/dichloromethane gradient over 30min) to afford the desired 3- (2-dispiro [2.0.2.1] as a slow solidifying pale orange resin ]Hept-7-ylethoxy) pyrrolidin-2-one (399mg, 76%).¹H NMR (400MHz, dimethylsulfoxide-d)₆) 7.74 (width s, 1H), 3.84(dd, J ═ 7.7, 7.1Hz, 1H), 3.71(dt, J ═ 9.2, 6.7Hz, 1H), 3.44(dt, J ═ 9.3, 6.8Hz, 1H), 3.22-3.01(M, 2H), 2.27(dtd, J ═ 12.8, 7.4, 3.7Hz, 1H), 1.78 (ddt, J ═ 12.8, 8.4, 7.1Hz, 1H), 1.57(q, J ═ 6.7Hz, 2H), 1.35(t, J ═ 6.6Hz, 1H), 0.87-0.70 (M, 4H), 0.67-0.55(M, 2H), 0.54-0.36 (ESI, 2H), MS-221.14159 (M/z + M + 2H)⁺(ii) a Retention time: 1.35min (LC method B).

Step 2: 2-chloro-6- [3- (2-dispiro [2.0.2.1] hept-7-ylethoxy) -2-oxo-pyrrolidin-1-yl ] pyridine-3-carboxylic acid tert-butyl ester

A100 mL flask was charged with a solution containing tert-butyl 2, 6-dichloropyridine-3-carboxylate (424mg, 1.709 mmol) and 3- (2-dispiro [2.0.2.1]]Hept-7-ylethoxy) pyrrolidin-2-one (376mg, 1.699mmol) in anhydrous N, N-dimethylformamide (4mL), potassium carbonate (724mg, 5.239mmol) was added (325 mesh), followed by 1, 4-diazabicyclo [2.2.2 ]]Octane (62mg, 0.5527 mmol.) the mixture was stirred at ambient temperature under nitrogen. After 16h, the reaction was quenched by addition of water (50mL) and then extracted with ethyl acetate (3 × 40 mL). The organic phase was dried over sodium sulfate, filtered, and the volatiles were evaporated Purify the product by flash chromatography on silica gel using a gradient of ethyl acetate/hexane (0 to 50% over 30 min.) the pure fractions are collected and the solvent is evaporated to give 2-chloro-6- [3- (2-dispiro [2.0.2.1] as a colorless resin]Hept-7-ylethoxy) -2-oxo-pyrrolidin-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (555mg, 75%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)8.33 (d, J ═ 8.6Hz, 1H), 8.24(d, J ═ 8.6Hz, 1H), 4.32(dd, J ═ 8.8, 7.9Hz, 1H), 4.07-3.94 (m, 1H), 3.86-3.64(m, 2H), 3.56(dt, J ═ 9.2, 6.8Hz, 1H), 2.49-2.38(m, 1H), 1.89 (dq, J ═ 12.5, 8.8, 1H), 1.62(q, J ═ 6.7Hz, 2H), 1.55(s, 9H), 1.39(t, J ═ 6.6Hz, 1H), 0.88-0.71(m, 4H), 0.69-0.57(m, 2H), 0.46(d, 8.8H, 2H). ESI-MS M/z calculated 432.18158, Experimental 433.3(M +1)⁺(ii) a Retention time: 2.43min (LC method B).

And step 3: 2-chloro-6- [3- (2-dispiro [2.0.2.1] hept-7-ylethoxy) -2-oxo-pyrrolidin-1-yl ] pyridine-3-carboxylic acid

A100 mL flask was charged with 2-chloro-6- [3- (2-dispiro [2.0.2.1]]Hept-7-ylethoxy) -2-oxo-pyrrolidin-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (533mg, 1.231mmol), dichloromethane (5mL) and trifluoroacetic acid (1.4 mL, 18.17mmol) (color turned quickly to brown). The reaction was diluted with dichloromethane and hexanes and volatiles were evaporated under reduced pressure the residue was triturated with dichloromethane/hexanes and volatiles were evaporated (the cycle repeated 3 times) to give 2-chloro-6- [3- (2-dispiro [2.0.2.1] as a light gray solid ]Hept-7-ylethoxy) -2-oxo-pyrrolidin-1-yl]Pyridine-3-carboxylic acid (479mg, 103% yield, 93% purity).¹H NMR (400MHz, dimethylsulfoxide-d)₆)13.51(s，1H)，8.34(d，J＝8.6Hz，1H)，8.31(d，J＝8.5Hz， 1H)，4.32(t，J＝8.3Hz，1H)，4.01(ddd，J＝11.2，8.8，2.8Hz，1H)，3.88-3.63(m，2H)， 3.56(dt，J＝9.3，6.7Hz，1H)，2.47-2.37(m，1H)，1.89(dq，J＝12.2，8.6Hz，1H)， 1.62(q，J＝6.7Hz，2H)，1.39(t，J＝6.5Hz, 1H), 0.93-0.69(M, 4H), 0.69-0.56(M, 2H), 0.46(d, J ═ 8.6Hz, 2H.) ESI-MS M/z calculated 376.119, experimental 377.1(M +1)⁺(ii) a Retention time: 1.83min (LC method B).

And 4, step 4: (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1] hept-7-ylethoxy) -2-oxo-pyrrolidin-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

A100 mL round bottom flask was charged with 2-chloro-6- [3- (2-dispiro [2.0.2.1] under nitrogen]Hept-7-ylethoxy) -2-oxo-pyrrolidin-1-yl]Pyridine-3-carboxylic acid (475mg, 1.261mmol) and anhydrous tetrahydrofuran (8 mL). Add carbonyldiimidazole (225mg, 1.388mmol) (freshly recrystallized from tetrahydrofuran) and stir the mixture at room temperature under nitrogen for 2 h.Add 150mg carbonyldiimidazole and stir the mixture at room temperature for 2 h.prepare (4S) -2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino under nitrogen in a separate 20mL flask]Propyl radical]A solution of pyrrolidine-1-carboxylic acid tert-butyl ester (520mg, 1.260mmol) in anhydrous tetrahydrofuran (4mL) and then added by syringe to the activated ester solution 1, 8-diazabicyclo [5.4.0 ] was added by syringe ]Undec-7-ene (0.95mL, 6.353mmol) and the reaction mixture was stirred at room temperature under a nitrogen atmosphere overnight. After 18h, the solvent was removed under reduced pressure and the resulting thick oil was treated with ethyl acetate (30mL) and water (30mL), aqueous hydrochloric acid (1.4mL, 6M, 8.400mmol) was slowly added (final pH ═ 5), and the two phases were separated, the aqueous phase was re-extracted with ethyl acetate (30mL), the combined organic extracts were washed with brine (30mL) and dried over sodium sulfate, after filtration and evaporation of the solvent, the residue (1.34g) was dissolved in dichloromethane and purified by silica gel flash chromatography using a gradient of ethyl acetate/hexane (0 to 100% over 30min), still yielding an impure product, which was further purified by silica gel flash chromatography using a gradient of ethyl acetate/hexane (0 to 100% over 30min) to yield (4S) -4 as a white foamy solid- [3- [ [6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1 ]]Hept-7-ylethoxy) -2-oxo-pyrrolidin-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (449 mg, 46%). ESI-MS M/z calculated 770.3229, Experimental 771.5(M +1)⁺(ii) a Retention time: 2.43 min (LC method B).

And 5: 2-chloro-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] propylamino ] -2-pyridinyl ] sulfonyl ] -6- [3- (2-dispiro [2.0.2.1] hept-7-ylethoxy) -2-oxo-pyrrolidin-1-yl ] pyridine-3-carboxamide (dihydrochloride)

A100 mL flask was charged with (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1]]Hept-7-ylethoxy) -2-oxo-pyrrolidin-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (440mg, 0.5704mmol), dichloromethane (5mL) and hydrochloric acid (800 μ L, 4M in dioxane, 3.200 mmol.) the reaction was stirred at room temperature for approximately 3 h. Volatiles were removed by vacuum evaporation. The residue was triturated with dichloromethane/hexane and the solvent was evaporated. This operation was repeated until a white solid was obtained. Vacuum drying to obtain 2-chloro-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] as white solid]Propylamino group]-2-pyridyl]Sulfonyl radical]-6- [3- (2-dispiro [2.0.2.1]]Hept-7-ylethoxy) -2-oxo-pyrrolidin-1-yl]Pyridine-3-carboxamide (dihydrochloride) (453mg, 107%). the product was used in the next step without any further purification.¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.75 (width s, 1H), 9.12(br s, 1H), 8.99(br s, 1H), 8.32(d, J ═ 8.5Hz, 1H), 8.02(dd, J ═ 8.5, 0.8Hz, 1H), 7.61(dd, J ═ 8.5, 7.2Hz, 1H), 7.26(br s, 1H)7.19-7.11(m, 1H), 6.75(dd, J ═ 8.5, 0.7, 1H), 4.32(t, J ═ 8.3Hz, 1H), 3.97(td, J ═ 8.8, 8.3, 4.7Hz, 1H), 3.84-3.65(m, 2H), 3.56(dt, J ═ 9.2, 6.7, 3.8, 3.7, 4.7Hz, 1H), 3.84-3.65(m, 2H), 3.56(dt, J ═ 9.2, 6.7, 3.88H), 3.81-2H (m, 1H), 1.49-2H), 1H (1H, 1H), 2H, 1H, 49 (1H). 62(q, J ═ 6.7Hz, 2H), 1.56-1.44(M, 3H), 1.44-1.33(M, 6H), 1.28-1.26(M, 3H), 0.82-0.76(M, 4H), 0.68-0.57(M, 2H), 0.53-0.39(M, 2H), ESI-MS M/z calculated 670.27045, experimental 671.4(M +1)⁺(ii) a Retention time: 1.65min (LC method B).

Step 6: (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione

A50 mL round bottom flask equipped with a magnetic stir bar was charged under nitrogen with 2-chloro-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] ester]Propylamino group]-2-pyridyl]Sulfonyl radical]-6- [3- (2-dispiro [2.0.2.1 ]]Hept-7-ylethoxy) -2-oxo-pyrrolidin-1-yl]Pyridine-3-carboxamide (dihydrochloride) (446mg, 0.5993mmol), anhydrous NMP (25mL), anhydrous potassium carbonate (615mg, 4.450mmol) (325 mesh). The mixture was stirred vigorously under nitrogen in a dry bath at 150 ℃ for 14h, then at 155 ℃ for 3h, then at 160 ℃ for 3.5h after cooling to room temperature, the mixture was poured into cold water (200mL) and acidified (slightly foamed) by addition of aqueous hydrochloric acid (1.5mL, 6M, 9.000 mmol). The resulting solid was filtered and air dried approximately the solid was dissolved in dichloromethane and the resulting cloudy solution was decanted to separate the remaining water and dried over sodium sulfate. After concentration, the residue was purified by flash chromatography on silica gel using a gradient of methanol/dichloromethane (0 to 5% over 30 min.) the solvent was evaporated, followed by trituration in dichloromethane/hexane and evaporation of the solvent to give (14S) -8- [3- (2- { dispiro [2.0.2.1 ] as a white solid ]Hept-7-yl } ethoxy) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (198mg, 52%). ESI-MS M/z calculated 634.29376, Experimental 635.4(M +1)⁺(ii) a Retention time:2.17min (LC method B).

And 7: (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 179) and (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 180)

By SFC chromatography using a ChiralPak OJ-H (250X 10mm) column (5 μm particle size) and a 20% acetonitrile/methanol (90: 10)/80% carbon dioxide mobile phase (10mL/min, over 8.0min) [ infusion volume 70 μ L, 24mg/mL solution in acetonitrile/methanol/dimethylsulfoxide (85: 9: 6) ]For (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Chiral separation of tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (200mg, 0.3088mmol) gave (14S) -8- [3- (2- { dispiro [2.0.2.1 ] as a white solid for the first diastereomer to be eluted]Hept-7-yl } ethoxy) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 179) (86mg, 43%, > 98% ee),¹h NMR (400MHz, dimethylsulfoxide-d)₆)12.43(s，1H)，7.70(d，J＝8.4 Hz，1H)，7.57(dd，J＝8.5，7.2Hz，1H)，7.51(d，J＝8.4Hz，1H)，7.04(d，J＝7.1Hz， 1H)，6.96(d，J＝9.0Hz，1H)，6.70(d，J＝8.5Hz，1H)，4.22(t，J＝7.9Hz，1H)，4.02 (ddd，J＝10.9, 8.6, 3.2Hz, 1H), 3.91(q, J ═ 11.4Hz, 1H), 3.79(dt, J ═ 9.2, 6.7Hz, 1H), 3.70(dt, J ═ 10.5, 7.5Hz, 1H), 3.55(dt, J ═ 9.2, 6.7Hz, 1H), 3.18-3.06(m, 1H), 2.94(d, J ═ 13.2Hz, 1H), 2.76-2.62(m, 1H), 2.40(dtd, J ═ 12.3, 7.2, 2.9Hz, 1H), 2.18-2.01(m, 1H), 1.97-1.86(m, 1H), 1.82(dd, J ═ 12.1, 5.4, 1H), 1.68(m, 1H), 1.49-1H), 1.49(m, 1H), 1.82(dd, 5.4, 1H), 1.49 (t, 1H), 1.1.1H), 1H), 1.49(m, 1H), 1.49 (t, 1.9H), 1H), 1.9H), 1.9H, 1H, 0.84-0.77 (m, 4H), 0.67-0.57(m, 2H), 0.50-0.41(m, 2H); ESI-MS M/z calculated 634.29376, Experimental 635.4(M +1) ⁺(ii) a Retention time: 2.19min (LC method B); and (14S) -8- [3- (2- { dispiro [2.0.2.1 ] as a white solid of the second diastereomer to be eluted]Hept-7-yl } ethoxy) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 180) (76mg, 38%, > 98% ee);¹h NMR (400MHz, dimethylsulfoxide-d)₆) 12.41(s, 1H), 7.70(d, J ═ 8.5Hz, 1H), 7.57(t, J ═ 7.9Hz, 1H), 7.52(d, J ═ 8.4Hz, 1H), 7.04(d, J ═ 7.2Hz, 1H), 6.96(s, 1H), 6.70(d, J ═ 8.5Hz, 1H), 4.27(t, J ═ 8.2Hz, 1H), 3.91(t, J ═ 9.9Hz, 2H), 3.78(t, J ═ 8.2Hz, 2H), 3.54(q, J ═ 8.2Hz, 1H), 3.14-3.04(m, 1H), 2.98-2.89(m, 1H), 2.72-2.63(m, 1H), 2.03-2H (m, 1H), 1H, 3.48-19 (m, 1H), 1.48-1H, 3.48 (m, 1H, 3.48, 1H, 3.48, 1H, 3, 2H) 0.83-0.76(m, 4H), 0.62(d, J ═ 8.9Hz, 2H), 0.46(d, J ═ 8.8Hz, 2H); ESI-MS M/z calculated 634.29376, Experimental 635.4 (M +1) ⁺(ii) a Retention time: 2.18min (LC method B).

Example 49: preparation of (14S) -12, 12-dimethyl-8- {3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy]-1H-pyrazol-1-yl } -2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1(23) 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (Compound 185)

Step 1: 1-chloro-2, 2, 3, 3-tetramethyl-1- (1, 2, 2-trichloroethylene) cyclopropane

To a microwave vial was added 2, 3-dimethylbut-2-ene (20.5mL, 172.5mmol) and 1, 2, 3, 3-tetrachlorocyclopropene (29.1g, 163.6mmol). The reaction vessel was sealed and heated at 155 ℃ for 16 h. The reaction was cooled to room temperature and transferred to a flask. The crude reaction was subjected to an interbulb vacuum distillation at 195 ℃ to provide 1-chloro-2, 2, 3, 3-tetramethyl-1- (1, 2, 2-trichloroethylene) cyclopropane (37.49g, 87%) as an orange liquid.¹H NMR (400MHz, chloroform-d) 1.25(s, 3H), 1.22(s, 3H), 1.20(s, 3H), 1.18(s, 3H).

Step 2: 3-ethynyl-1, 1, 2, 2-tetramethyl-cyclopropane

To a 500mL round bottom flask were added 1-chloro-2, 2, 3, 3-tetramethyl-1- (1, 2, 2-trichloroethenyl) cyclopropane (17.4g, 66.41mmol) and diethyl ether (300 mL). The reaction was cooled to-78 ℃ and the reaction was stirred for 15 min. N-butyllithium solution (118mL, 2.5M, 295.0mmol) was added dropwise over 30min and the mixture was allowed to warm to room temperature over 2h and stirred at room temperature for 1h, the reaction was cooled to-10 ℃ and water (35mL, 1.943mol) was added dropwise and the mixture was stirred and warmed to room temperature over 30 min. The reaction was extracted with ether, dried over sodium sulfate, filtered and evaporated the crude reaction mixture was purified by vacuum distillation at 80 ℃ to afford 3-ethynyl-1, 1, 2, 2-tetramethyl-cyclopropane (6.059g, 75%). ¹H NMR(400 MHz, chloroform-d) 1.96(d, J ═ 2.2Hz, 1H), 1.11(d, J ═ 3.8Hz, 12H), 0.86(d, J ═ 0.9Hz, 1H).

And step 3: 2- (2, 2, 3, 3-tetramethylcyclopropyl) ethanol

To an anhydrous round bottom flask were added 3-ethynyl-1, 1, 2, 2-tetramethyl-cyclopropane (4.1g, 33.55mmol) and tetrahydrofuran (25mL), the reaction was cooled for 5min in a-30 ℃ bath, a solution of borane in tetrahydrofuran (33.6mL, 1M, 33.60mmol) was added dropwise, and the reaction was allowed to warm to room temperature over 30 min. The reaction was cooled to-10 ℃ and sodium hydroxide (28.5mL, 6M, 171.0mmol) was added carefully followed by hydrogen peroxide (38mL, 30% w/v, 335.1 mmol). The reaction was stirred for 30min while warming to room temperature. The reaction was extracted with ether, dried over sodium sulfate, filtered and evaporated to afford the crude aldehyde intermediate. Methanol (40mL) was added to the crude aldehyde. The reaction was cooled to 0 ℃ and sodium borohydride (2.54g, 67.14mmol) was added portionwise. The reaction was stirred for 1h while warming to room temperature. The reaction was quenched with a saturated solution of ammonium chloride and brine and extracted with ether the organic layer was dried over sodium sulfate, filtered and evaporated to afford 2- (2, 2, 3, 3-tetramethylcyclopropyl) ethanol as an oil (1.800g, 38%). ¹H NMR (400MHz, chloroform-d) 3.64(t, J ═ 6.9Hz, 2H), 1.54(q, J ═ 7.0Hz, 2H), 1.06(s, 6H), 0.93(s, 6H), 0.13(t, J ═ 7.1Hz, 1H). ESI-MS M/z calculated 142.13577, Experimental 143.1(M +1)⁺(ii) a Retention time: 1.49min (LC method B).

And 4, step 4: 3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy ] pyrazole-1-carboxylic acid tert-butyl ester

To 5-oxo-1H-pyrazole-2-carboxylic acid tert-butyl ester (884mg, 4.799mmol) and 2- (2, 2, 3, 3-tetramethylcyclopropyl) ethanol650mg, 4.570mmol) in tetrahydrofuran (10mL) triphenylphosphine (1.26g, 4.804mmol) was added to the mixture slowly and dropwise diisopropyl azodicarboxylate (970mg, 4.797mmol) over 2min at room temperature (exotherm noted), the reaction mixture was stirred at room temperature for 30min, the tetrahydrofuran was removed in vacuo and toluene (30mL) was added and the mixture was stirred overnight no precipitate was observed, and the mixture was evaporated and purified by silica gel chromatography (0% to 50% ethyl acetate/hexane gradient) to give 3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy ] n]Pyrazole-1-carboxylic acid tert-butyl ester (700mg, 50%).¹H NMR (400MHz, chloroform-d) 7.82(d, J ═ 2.9Hz, 1H), 5.86(d, J ═ 2.9Hz, 1H), 4.27(t, J ═ 7.2Hz, 2H), 1.72(q, J ═ 7.2Hz, 2H), 1.61(s, 10H), 1.05(s, 6H), 0.95(s, 6H), 0.22(t, J ═ 7.2Hz, 1H). ESI-MS M/z calculated 308.21, Experimental 309.24(M +1) ⁺(ii) a Retention time: 0.89 min (LC method A).

And 5: 3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy ] -1H-pyrazole

To 3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy]To a solution of pyrazole-1-carboxylic acid tert-butyl ester (700mg, 2.270 mmol) in methanol (7.0mL) was added sodium hydroxide (2.35mL, 2M, 4.700mmol) and the mixture was stirred at ambient temperature for 30 min. Most of the methanol was removed in vacuo and the residue diluted with water (14mL) and aqueous hydrochloric acid (4.5mL, 1M, 4.500 mmol). The mixture was extracted with ethyl acetate and the organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a pale yellow oil, i.e., 3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy ] ethoxy]-1H-pyrazole (471mg, 100%), which was used directly in the next step. ESI-MS M/z calculated 208.15756, Experimental 209.2(M +1)⁺(ii) a Retention time: 1.77 min (LC method E).

Step 6: 2-chloro-6- [3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy ] pyrazol-1-yl ] pyridine-3-carboxylic acid ethyl ester

Ethyl 2, 6-dichloropyridine-3-carboxylate (494mg, 2.245mmol) and 3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy]-1H-pyrazole (471mg, 2.261mmol) and potassium carbonate (373mg, 2.699mmol) were combined in anhydrous dimethylsulfoxide (10 mL). Addition of 1, 4-diazabicyclo [2.2.2 ]Octane (50.5mg, 0.4502mmol) and the mixture was stirred at room temperature under nitrogen for 20h the reaction mixture was diluted with water (16mL) and stirred for 15 min the resulting white solid was collected by filtration and washed with water. The mixture was filtered and evaporated to provide 2-chloro-6- [3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy ] ethanol as an off-white solid]Pyrazol-1-yl]Pyridine-3-carboxylic acid ethyl ester (800mg, 91%).¹H NMR (400 MHz, chloroform-d) 8.36(d, J ═ 2.9Hz, 1H), 8.27(d, J ═ 8.4Hz, 1H), 7.72(d, J ═ 8.5Hz, 1H), 5.97(d, J ═ 2.9Hz, 1H), 4.41(q, J ═ 7.2Hz, 2H), 4.25(t, J ═ 7.2Hz, 2H), 1.77 (q, J ═ 7.2Hz, 2H), 1.42(t, J ═ 7.2Hz, 3H), 1.08(s, 6H), 0.97(s, 6H), 0.25(t, J ═ 7.2Hz, 1H), ESI-M/z calculated value 391.16626, experimental value 392.2(M +1)⁺(ii) a Retention time: 2.25min (LC method E).

And 7: 2-chloro-6- [3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy ] pyrazol-1-yl ] pyridine-3-carboxylic acid

Treatment of a sample containing 2-chloro-6- [3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy group with sodium hydroxide (2.0mL, 2M, 4.000mmol)]Pyrazol-1-yl]Ethyl pyridine-3-carboxylate (800mg, 2.041mmol) in tetrahydrofuran (4.000 mL) and ethanol (1.600mL) and the solution was stirred at room temperature for 1 h. Most of the solvent was removed under reduced pressure, and the solution was acidified by slowly adding citric acid (8.0mL, 10% w/v, 4.164mmol) under ice-cooling. The resulting thick suspension (pH about ═ 3) was stirred in an ice bath for 1h, filtered and concentrated And washed with excess water. The collected solid was completely dissolved in dichloromethane, dried over sodium sulfate, filtered, and concentrated to dryness using toluene as an azeotrope, and further dried under vacuum for 21h to give 2-chloro-6- [3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy ] as a white solid]Pyrazol-1-yl]Pyridine-3-carboxylic acid (710mg, 96%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)13.56(s, 1H), 8.52-8.29(M, 2H), 7.72(d, J ═ 8.4 Hz, 1H), 6.18(d, J ═ 2.8Hz, 1H), 4.23(t, J ═ 6.8Hz, 2H), 1.72(q, J ═ 7.0Hz, 2H), 1.04(s, 6H), 0.95(s, 6H), 0.27(t, J ═ 7.2Hz, 1H), ESI-MS M/z calculated value 363.13498, experimental value 364.2(M +1)⁺(ii) a Retention time: 2.35min (LC method G).

And 8: (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy]Pyrazol-1-yl]Pyridine-3-carboxylic acid (255 mg, 0.7009mmol) and carbonyldiimidazole (125mg, 0.7709mmol) were combined in tetrahydrofuran (5.738mL) and stirred at room temperature for 90min (4S) -2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino ]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (350mg, 0.8484mmol) followed by addition of anhydrous 1, 8-diazabicyclo [5.4.0]Undec-7-ene (275 μ L, 1.839mmol) and the reaction stirred at room temperature for 20 h. The organics were separated, dried over sodium sulfate, filtered and evaporated under reduced pressure followed by chromatography on silica gel using a gradient of 100% hexane to 80% ethyl acetate/hexane to give (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy ] as a white solid]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester(s) (iii)261mg, 49%). ESI-MS M/z calculated 757.3388, Experimental 758.5(M +1)⁺(ii) a Retention time: 2.43min (LC method G).

And step 9: (14S) -12, 12-dimethyl-8- {3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy]-1H-pyrazol-1-yl } -2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 185)

Mixing (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy ]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (115 mg, 0.1516mmol), potassium carbonate (125mg, 0.9045mmol),

Molecular sieves and dimethylsulfoxide (4mL) were combined in a vial, purged with nitrogen, capped, heated to 160 ℃ and stirred for 72h, cooled to room temperature filtered the mixture, and the filtrate was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate, followed by brine the organics were separated, dried over sodium sulfate and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexane to 70% ethyl acetate/hexane to give (14S) -12, 12-dimethyl-8- {3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy ] as an off-white solid]-1H-pyrazol-1-yl } -2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 185) (18.14mg, 19%).¹H NMR (400MHz, chloroform-d) 9.96(s, 1H), 8.20(d, J ═ 2.8Hz, 1H), 8.07(d, J ═ 8.3Hz, 1H), 7.60-7.49(m, 2H), 7.36-7.23 (m, 2H), 6.56(d, J ═ 8.0Hz, 1H), 5.92(d, J ═ 2.9Hz, 1H), 4.82-4.58(m, 1H), 4.25(t, J ═ 7.2Hz, 2H), 4.00-3.76(m, 1H), 3.35(t, J ═ 8.8Hz, 1H), 3.17(d, J ═ 14.3 Hz, 1H), 3.07(t, J ═ 9.8Hz, 1H), 2.73-2.50(M, 1H), 2.09(dd, J ═ 12.3, 7.9Hz, 1H), 1.76(q, J ═ 7.1Hz, 2H), 1.65-1.59(M, 6H), 1.53-1.41(M, 2H), 1.08(s, 6H), 0.97 (s, 6H), 0.90-0.81(M, 2H), 0.25(t, J ═ 7.2Hz, 1H), ESI-MS M/z calculated 621.30975, experimental 622.2(M +1)⁺(ii) a Retention time: 2.22min (LC method B).

Example 50: preparation of (18S) -4- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-20, 20-dimethyl-10. lambda.⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac 2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (Compound 187)

Step 1: (4S) -2, 2-dimethyl-4- [3- (3-sulfamoylpyrazol-1-yl) propyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

Racemic 2, 2-dimethyl-4- [3- (3-sulfamoylpyrazol-1-yl) propyl ] was chromatographed by SFC using ChiralPak IG (250 × 21.2mm column, 5 μm particle size) and a 28% methanol/72% carbon dioxide mobile phase (70mL/min over 14.0min) (injection volume 500 μ L, 32mg/mL solution in methanol)]Pyrrolidine-1-carboxylic acid tert-butyl ester (3.24g, 8.383mmol) was subjected to chiral separation to give (4S) -2, 2-dimethyl-4- [3- (3-sulfamoylpyrazol-1-yl) propyl ] as the second enantiomer to be eluted ]Pyrrolidine-1-carboxylic acid tert-butyl ester (1.45g, 90%).¹H NMR(400MHz，CDCl₃)7.42(d, J ═ 2.4Hz, 1H), 6.72(d, J ═ 2.5Hz, 1H), 5.08(s, 2H), 4.22-4.12(M, 2H), 3.64(t, J ═ 9.1Hz, 1H), 2.80(t, J ═ 10.8Hz, 1H), 2.05(s, 1H), 1.99-1.80(M, 3H), 1.58(s, 1H), 1.45(d, J ═ 2.3Hz, 9H), 1.40(d, J ═ 11.4Hz, 4H), 1.27(s, 4H), ESI-MS M/z calculated value 386.19876, experimental value 387.1(M +1)⁺(ii) a Retention time: 1.52min (LC method B).

Step 2: (4S) -4- [3- [3- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1] hept-7-ylethoxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] pyrazol-1-yl ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- (2-dispiro [2.0.2.1]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (1.35g, 3.752mmol) and carbonyldiimidazole (761.1mg, 4.694mmol) (newly recrystallized from tetrahydrofuran, washed with low temperature ether and dried under high vacuum) were combined in tetrahydrofuran (17.55mL) and stirred at room temperature for 50min, then (4S) -2, 2-dimethyl-4- [3- (3-sulfamoylpyrazol-1-yl) propyl ] was added]Pyrrolidine-1-carboxylic acid tert-butyl ester (1.45g, 3.752mmol) in tetrahydrofuran (6.75mL) followed by the addition of 1, 8-diazabicyclo [5.4.0 ]Undec-7-ene (2.857g, 18.77mmol) and the reaction stirred at room temperature for 16h tetrahydrofuran was removed by rotary evaporation and dissolved in ethyl acetate and washed with saturated aqueous ammonium chloride solution (1 ×), then brine (1 ×), dried (sodium sulfate), filtered and concentrated to a white solid which was subjected to 275g C eluting with a gradient of 50-100% acetonitrile/water₁₈Reverse phase column chromatography the product was eluted in both the pure and mixed fractions with starting material, hyaluronic acid. The pure fractions were combined, concentrated, then partitioned between 6N hydrochloric acid and ethyl acetate the layers were separated, the aqueous phase was washed again with ethyl acetate, then the organic phases were combined, dried (sodium sulfate), filtered and concentrated to a white solid. The combined fractions from the reverse phase column were combined and concentrated under reduced pressure the residue was partitioned between 6N hydrochloric acid and ethyl acetate the layers were separated, the aqueous phase was washed again with ethyl acetate, the organic phases were then combined, dried (sodium sulfate), filtered and concentrated to a white solid which was subjected to 275g C eluting with a gradient of 50-100% acetonitrile/water₁₈And (4) performing reversed phase column chromatography. The pure fractions were combined, concentrated and added to the pure material from the first column to give (4S) -4- [3- [3- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1 ] ]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Pyrazol-1-yl]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.96g, 72%).¹H NMR(400MHz，CDCl₃)9.50(s, 1H), 8.30(d, J ═ 2.9Hz, 1H), 8.26(d, J ═ 8.5Hz, 1H), 7.75(d, J ═ 8.5Hz, 1H), 7.47(d, J ═ 2.4Hz, 1H), 7.05(d, J ═ 2.4Hz, 1H), 5.96(d, J ═ 2.9Hz, 1H), 4.25(t, J ═ 6.8Hz, 2H), 4.20(t, J ═ 7.1Hz, 2H), 3.66(s, 1H), 2.83(t, J ═ 10.6Hz, 1H), 2.06(d, J ═ 9.7Hz, 1H), 1.90(p, J ═ 7.2, 5H), 1.48 (t, 6Hz, 1H), 1.35H, 6H, 1H, 2.06(d, J ═ 9.7, 1H), 1.90(p, J ═ 7.2, 5H, 6H, 1H), 0.6H, 1H, 2.87 (d, 0.6, 2.6H), 2.6H, 1H, 2.6H, 1H, 2.6H, 1. ESI-MS M/z calculated 727.2919, Experimental 728.1(M +1)⁺(ii) a Retention time: 0.91min (LC method A).

And step 3: 2-chloro-N- [1- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] propyl ] pyrazol-3-yl ] sulfonyl-6- [3- (2-dispiro [2.0.2.1] hept-7-ylethoxy) pyrazol-1-yl ] pyridine-3-carboxamide

Mixing (4S) -4- [3- [3- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Pyrazol-1-yl]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.96g, 2.691 mmol) was dissolved in dichloromethane (8.553mL) and trifluoroacetic acid (8.291mL, 107.6mmol) was added to the mixture and the mixture was stirred at room temperature for 60min. The organic layer was concentrated by rotary evaporation, followed by high vacuum pump to give 2-chloro-N- [1- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] as a yellow solid ]Propyl radical]Pyrazol-3-yl]Sulfonyl-6- [3- (2-dispiro [2.0.2.1 ]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carboxamide (1.84g, 109%). ESI-MS M/z calculated 627.23944, Experimental 628.1(M +1)⁺(ii) a Retention time: 0.65min (LC method A).

And 4, step 4:(18S) -4- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-20, 20-dimethyl-10. lambda.⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac 2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (Compound 187)

2-chloro-N- [1- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl group]Propyl radical]Pyrazol-3-yl]Sulfonyl-6- [3- (2-dispiro [2.0.2.1 ]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carboxamide (1.69g, 2.690mmol), potassium carbonate (1.859g, 13.45mmol), cesium fluoride (614.9mg, 4.048mmol),

Molecular sieves and dimethylsulfoxide (102.5mL) were combined in a vial, purged with nitrogen, capped, heated to 155 ℃ and stirred for 18 h. Cooled to room temperature and the mixture was filtered, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, followed by brine the organics were separated, dried over sodium sulfate, evaporated and then purified by silica gel chromatography using a gradient of 100% hexane to 100% ethyl acetate to give (18S) -4- [3- (2- { dispiro [2.0.2.1 ] as a white solid ]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-20, 20-dimethyl-10. lambda.⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac 2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (compound 187) (1.14g, 72%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.69 (s, 1H), 8.17(d, J ═ 2.8Hz, 1H), 8.00(d, J ═ 2.3Hz, 1H), 7.71(d, J ═ 8.2Hz, 1H), 6.91-6.84(m, 2H), 6.06(d, J ═ 2.7Hz, 1H), 4.21(qd, J ═ 7.2, 6.6, 2.7Hz, 3H), 4.13 (dd, J ═ 13.7, 11.3Hz, 1H), 2.72-2.62(m, 1H), 2.09(d, J ═ 12.0Hz, 2H), 1.94-1.84 (m, 1H), 1.84-1.75(m, 5H), 1.55(s, 3H), 1.47(s, 3H), 1.43 (s, 1H), 1.47 (t, 1.47, 2H), 2.47 (m, 3H), 4.47 (m, 2H), 3H, 8.47 (m, 8, 3H), 3H, 8 (dd, 3H), 3H), 3H, 2H, 8.49 (1H), 2H), 3H, 8Calculations 591.26276, Experimental values 592.1(M +1)⁺(ii) a Retention time: 2.34min (LC method B).

Example 51: preparation of 8- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl]-12, 12, 18-trimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (Compound 189)

To a solution of tert-butyl 4- (3-hydroxypropyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (1.0g, 3.885mmol) in dichloromethane (25mL) was slowly added under nitrogen atmosphere at 0 ℃ bose-martin periodinane (2.0g, 4.715 mmol). The resulting heterogeneous reaction mixture was allowed to slowly warm to room temperature and stirred for an additional 2h the reaction mixture was diluted with diethyl ether and filtered through a pad of celite the filtrate was concentrated and the residue was purified by a short plug of silica gel using a 1: 1 mixture of hexane and ether to give tert-butyl 2, 2-dimethyl-4- (3-oxopropyl) pyrrolidine-1-carboxylate (992mg, 100%) as a colorless viscous oil. ESI-MS M/z calculated 255.18344, Experimental 256.2(M +1)⁺(ii) a Retention time: 0.64min (LC method A).

Step 2: 2, 2-dimethyl-4- [3- (methylamino) propyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 2, 2-dimethyl-4- (3-oxopropyl) pyrrolidine-1-carboxylate (500mg, 1.958mmol) in dichloromethane (10mL) was added sodium acetate (241mg, 2.938mmol), followed byMethylamine (1.2 mL, 2M, 2.400mmol) was added the reaction mixture was stirred at room temperature for 1h and cooled to 0 ℃ and sodium cyanoborohydride (372mg, 5.920mmol) was added under a nitrogen atmosphere. The heterogeneous reaction mixture was slowly warmed to room temperature and stirred for a further 16 h. The reaction mixture was quenched with water and extracted slowly with diethyl ether the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The reaction mixture was purified by reverse phase HPLC-MS method using a double gradient run of 20-80% mobile phase B (mobile phase a ═ water (5mM hydrochloric acid), mobile phase B ═ acetonitrile) over 15.0min to give 2, 2-dimethyl-4- [3- (methylamino) propyl ] as a viscous oil ]Pyrrolidine-1-carboxylic acid tert-butyl ester (154mg, 29%).¹H NMR (400MHz, chloroform-d) 3.80-3.53 (m, 1H), 3.04-2.81(m, 3H), 2.69(q, J ═ 4.8Hz, 3H), 2.13(s, 1H), 1.89(s, 3H), 1.80 (s, 2H), 1.45(d, J ═ 10.5Hz, 12H), 1.38(s, 2H), 1.29(s, 3H). ESI-MS M/z calculated 270.23074, Experimental 271.3(M +1)⁺(ii) a Retention time: 0.47min (LC method A).

And step 3: 2, 2-dimethyl-4- [3- [ methyl- (6-sulfamoyl-2-pyridyl) amino ] propyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

To 2, 2-dimethyl-4- [3- (methylamino) propyl group]Pyrrolidine-1-carboxylic acid tert-butyl ester (154mg, 0.5695 mmol) to a solution in dimethyl sulfoxide (2mL) was added 6-fluoropyridine-2-sulfonamide (103mg, 0.5847 mmol) followed by diisopropylethylamine (500 μ L, 2.871 mmol.) the flask was capped with a septum and heated under nitrogen (balloon) in an oil bath at 90 ℃ for 14h. the reaction mixture was cooled to room temperature, then diluted with ethyl acetate and washed with brine solution, dried over sodium sulfate, filtered and evaporated. the resulting residue was purified by silica gel chromatography using a gradient of 100% hexane to 100% ethyl acetate to give 2, 2-dimethyl-4- [3- [ methyl- (6-sulfamoyl-2-pyridyl) amino as a white solid ]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (141mg, 58%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)7.65(dd, J ═ 8.6, 7.2Hz, 1H), 7.12 (s, 2H), 7.01(d, J ═ 7.2Hz, 1H), 6.78(d, J ═ 8.7Hz, 1H), 3.53(q, J ═ 7.8, 7.4Hz, 3H), 3.17(d, J ═ 3.6Hz, 1H), 3.04(s, 3H), 2.84-2.72(m, 1H), 2.09(d, J ═ 9.5Hz, 1H), 1.88(td, J ═ 12.8, 5.7Hz, 1H), 1.53(dt, J ═ 14.6, 7.4Hz, 2H), 1.36(dd, J ═ 15.0, 10.6, 14H), 1.23H (s, 3H). ESI-MS M/z calculated 426.23007, Experimental 427.3(M +1)⁺(ii) a Retention time: 0.47min (LC method A).

And 4, step 4: 4- [3- [ [6- [ [ 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] -methyl-amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

In a 20mL scintillation vial, 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (141mg, 0.3858mmol) and carbonyldiimidazole (65mg, 0.4009mmol) were combined in tetrahydrofuran (2 mL) and stirred at room temperature for 2 h. Followed by addition of 2, 2-dimethyl-4- [3- [ methyl- (6-sulfamoyl-2-pyridyl) amino]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (134mg, 0.3141mmol) followed by the addition of 1, 8-diazabicyclo [5.4.0 ]Undec-7-ene (100 μ L, 0.6687mmol) and the reaction stirred at room temperature for 16 h. The reaction was diluted with ethyl acetate and washed with a small amount of 1: 1 saturated aqueous ammonium chloride solution/brine. The organics were separated, dried over sodium sulfate, filtered and evaporated. The resulting brown residue was purified by silica gel chromatography using a gentle gradient from 100% dichloromethane to 20% methanol/dichloromethane to give 4- [3- [ [6- [ [ 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl ] as a white solid]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]-methyl-amino]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (158mg, 65%).¹H NMR (400MHz, chloroform-d) 8.29(d, J ═ 2.8Hz, 1H), 7.98(d, J ═ 8.4Hz, 1H), 7.77-7.60(m, 2H), 7.52(d, J ═ 7.2Hz, 1H), 6.64(d, J ═ 8.6Hz, 1H), 5.98-5.91(m, 1H), 4.42(dt, J ═ 8.3, 6.8Hz, 2H),4.14-4.04(M, 1H), 3.91(d, J ═ 13.9Hz, 1H), 3.32-3.21(M, 1H), 3.01(s, 3H), 2.91(t, J ═ 10.7Hz, 1H), 2.18(d, J ═ 12.8Hz, 1H), 2.02-1.93(M, 2H), 1.79(td, J ═ 16.6, 14.4, 6.6Hz, 2H), 1.65-1.48(M, 2H), 1.37(s, 9H), 1.30(s, 3H), 1.25(s, 3H), 1.22-1.14(M, 2H), 0.67(td, J ═ 13.3, 6.7, 3.6, 2H), 0.49-0.39(M, 4H), 0.37 (M, 0.84H), 0.7 (M, 2H), 0.83-1.5 (M, 5H), 2H, 17H, 5(M, 1H), 2H, 17H, 5H, 2H), calculated values (M, 1H, 3H, 1.8H, 3H), 1.8, 3H, 1.8, 1H, 3H ⁺(ii) a Retention time: 0.67min (LC method A).

And 5: 8- [3- (3, 3-Dicyclopropylpropoxy) -1H-pyrazol-1-yl]-12, 12, 18-trimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (Compound 189)

4- [3- [ [6- [ [ 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl ] is reacted at room temperature]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]-methyl-amino]Propyl radical]A solution of tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (153mg, 0.1986mmol) in dichloromethane (1.2mL) and trifluoroacetic acid (150.0 μ L, 1.960mmol) was stirred for 4h then the solvent was removed in vacuo the residue was dissolved in ethyl acetate, washed with a saturated solution of 2mL sodium bicarbonate and the solvent was removed and dried under high vacuum. The resulting residue was dissolved in dimethyl sulfoxide (8 mL) and added

Molecular sieves and stirring the reaction mixture for 10min then cesium fluoride (98mg, 0.6451mmol) and potassium carbonate (91mg, 0.6584mmol) are added and the reaction mixture is heated at 130 ℃ overnight the reaction mixture is filtered through Whatman filter disc (puradisc 25 TF) and the filter is purified by reverse phase HPLC-MS method using a double gradient run of 20-80% mobile phase B over 15.0min (mobile phase a ═ water (0.05% hydrochloric acid), mobile phase B ═ acetonitrile) Liquid to give 8- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl as an off-white solid]-12, 12, 18-trimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 189) (76mg, 60%).¹H NMR (400MHz, chloroform-d) 10.54(s, 1H), 8.19(d, J ═ 2.8Hz, 1H), 8.13(d, J ═ 8.4Hz, 1H), 7.67(dd, J ═ 8.6, 7.3Hz, 1H), 7.60-7.54(m, 1H), 7.37(d, J ═ 8.4Hz, 1H), 6.69(dd, J ═ 8.7, 0.8Hz, 1H), 5.92(d, J ═ 2.8Hz, 1H), 4.43(t J ═ 6.8Hz, 2H), 4.37(s, 1H), 3.37(dd, J ═ 9.8, 7.2Hz, 1H), 3.13-3.05(m, 1H), 3.01(s, 2H), 3.5.5 (dd, 5, 5.2 Hz, 1H), 3.6, 1H, 3.65 (dd ═ 6, 3.8, 3.5, 3, 5, 3.2 Hz, 1H), 3.6, 1H, 2H, 3.6, 1H, 3.6, 2H, 3, 3.65 (dd, 3, 2H), 3.5, 1H, 3.6, 1H, 2H, 1H, 2, 1.50-1.40(M, 4H), 0.72-0.59(M, 2H), 0.50-0.39(M, 4H), 0.34(ddd, J ═ 15.9, 9.0, 6.9Hz, 1H), 0.23-0.16(M, 2H), 0.15-0.07(M, 2H), ESI-MS M/z calculated 633.30975, experimental 634.22(M +1)⁺(ii) a Retention time: 1.55min (LC method J).

Example 52: preparation of (14R) -8- [3- (2- { dispiro [2.0.2.1]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (Compound 194)

Step 1: (4R) -2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino ] propyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

By SFC chromatography using ChiralPak IG (250X 21.2mm column, 5 μm particle size) and a 40% methanol/60% carbon dioxide mobile phase: (70mL/min over 11.0min) (injection volume 500 μ L of 32mg/mL solution in methanol) to racemic 2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (7g, 16.97mmol) was subjected to chiral separation to give (4R) -2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino group as the second enantiomer to be eluted]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (3.167g, 90%). ESI-MS M/z calculated 412.21442, experimental 413.2(M +1)⁺(ii) a Retention time: 0.63min (LC method A).

Step 2: (4R) -4- [3- [ [6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1] hept-7-ylethoxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To 2-chloro-6- [3- (2-dispiro [2.0.2.1 ]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (1.95g, 5.420 mmol) in tetrahydrofuran (20mL) carbonyl diimidazole (1.03g, 6.073mmol) was added and the mixture was stirred at ambient temperature for 1h to this mixture (4R) -2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino]Propyl radical]A solution of pyrrolidine-1-carboxylic acid tert-butyl ester (1.95g, 4.301mmol) in tetrahydrofuran (9mL) was then added 1, 8-diazabicyclo [5.4.0]Undec-7-ene (2.0mL, 13.37mmol) and the mixture stirred at ambient temperature for 16h the reaction was diluted with water (50mL) and the mixture was acidified with hydrochloric acid (5mL, 6M, 30.00 mmol). The mixture was extracted with ethyl acetate (200mL) and the organic phase was separated. The organic phase was washed with brine and the combined aqueous phases were back-extracted with 50mL ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product obtained was subjected to 275g C₁₈Performing reverse phase column chromatography, eluting with 50-100% acetonitrile/water. The product fractions were collected and concentrated in vacuo to give (4R) -4- [3- [ [6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1 ]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl ]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.73g, 65%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.76(s, 1H), 8.38(t, J ═ 2.3Hz, 1H), 8.11(d, J ═ 8.3Hz, 1H), 7.70(d, J ═ 8.3Hz, 1H), 7.62(dd, J ═ 8.5, 7.2Hz, 1H), 7.18(dd, J ═ 12.6, 6.3Hz, 2H), 6.74(d, J ═ 8.5Hz, 1H), 6.16(dd, J ═ 2.9, 1.4Hz, 1H), 4.24(t, J ═ 6.6Hz, 2H), 3.57-3.44(m, 1H), 3.24(t, J ═ 6.0Hz, 2H), 2.74(t, J ═ 10.5, 1H), 2.01(t, 2H), 1H), 3.9, 6.9H, 9H, 1H, 9H, 1H, 9H, 1H, 6H, 9H, 1H, 9H, 1H, 9H, 1H, 9H, 6H, 2H) 0.54-0.44 (M, 2H). ESI-MS M/z calculated 753.30756, Experimental 754.4(M +1)⁺(ii) a Retention time: 3.69min (LC method D).

And step 3: 2-chloro-N- [ [6- [3- [ (3R) -5, 5-dimethylpyrrolidin-3-yl ] propylamino ] -2-pyridinyl ] sulfonyl ] -6- [3- (2-dispiro [2.0.2.1] hept-7-ylethoxy) pyrazol-1-yl ] pyridine-3-carboxamide (trifluoroacetate)

To (4R) -4- [3- [ [6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carbonyl ]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.73g, 3.619mmol) in dichloromethane (15mL) and toluene (5mL) trifluoroacetic acid (3mL, 38.94mmol) was added and the mixture stirred at ambient temperature for 48 h. The solvent was removed in vacuo at a bath temperature set at 45 ℃ to give a thick yellow oil. The oil was diluted with toluene (20mL) and the solvent was removed in vacuo at a bath temperature set at 45 ℃ to give 2-chloro-N- [ [6- [3- [ (3R) -5, 5-dimethylpyrrolidin-3-yl ] as an oil]Propylamino group]-2-pyridyl]Sulfonyl radical]-6- [3- (2-dispiro [2.0.2.1 ]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carboxamide (trifluoroacetate) (2.78g, 100%) was used without further purification.¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.78(s，1H)，8.61(s，2H)，8.39(d，J＝2.9Hz，1H)，8.11(d，J＝8.4 Hz，1H)，7.71(d，J-8.3 Hz, 1H), 7.63(dd, J-8.5, 7.2Hz, 1H), 7.34-7.11(M, 5H), 6.75(dd, J-8.6, 0.7Hz, 1H), 6.18(d, J-2.9 Hz, 1H), 4.24(t, J-6.7 Hz, 2H), 3.36 (dt, J-11.6, 6.1Hz, 1H), 3.25(q, J-6.6 Hz, 2H), 2.89-2.71(M, 1H), 2.30(s, ddh), 1.93 (J-12.9, 7.6Hz, 1H), 1.89-1.71(M, 2H), 1.48(q, J-7.6H), 3.6H, 1.89-1.71(M, 2H), 1.48(q, 7.6H, 654H), 0.5H, 0.9, 0.5H), 0.5H, 1H, 4H, 5H, 4H, 5H, 0.5H, 1H, 4H, M, 1H, 4H, 1H, 4H, 1H ⁺(ii) a Retention time: 2.49min (LC method D).

And 4, step 4: (14R) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (Compound 194)

To 2-chloro-N- [ [6- [3- [ (3R) -5, 5-dimethylpyrrolidin-3-yl ] group]Propylamino group]-2-pyridyl]Sulfonyl radical]-6- [3- (2-dispiro [2.0.2.1 ]]Hept-7-ylethoxy) pyrazol-1-yl]To a solution of pyridine-3-carboxamide (trifluoroacetate) (2.78g, 3.619mmol) in NMP (50mL) was added potassium carbonate (2.5g, 18.09 mmol). The mixture was purged with nitrogen for 5min, the mixture was heated at 135 ℃ for 22 h. The reaction mixture was cooled to room temperature and added to water (150 mL). The mixture was carefully acidified with hydrochloric acid (7mL, 6M, 42.00mmol) to give a multivesicular slurry. The solid was collected by filtration using a medium pore frit. The wet cake was dissolved in ethyl acetate (200mL), washed with 100mL brine, and concentrated in vacuo. The crude product was diluted with acetonitrile and subjected to 250g of reverse phase C18 column chromatography eluting with 50-100% water/acetonitrile to give a foam which was dried in a vacuum oven at 45 ℃ for 48h to give (14R) -8- [3- (2- { dispiro [2.0.2.1 ] ]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9,19(23), 20-hexaen-2, 2, 4-trione (Compound 194) (1.3g, 57%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.51(s, 1H), 8.20(d, J ═ 2.8Hz, 1H), 7.82(d, J ═ 8.3 Hz, 1H), 7.58(dd, J ═ 8.5, 7.2Hz, 1H), 7.05(d, J ═ 7.2Hz, 1H), 6.99(d, J ═ 8.9Hz, 1H), 6.91(d, J ═ 8.2Hz, 1H), 6.71(d, J ═ 8.4Hz, 1H), 6.09(d, J ═ 2.7Hz, 1H), 4.21 (td, J ═ 6.6, 1.4Hz, 2H), 3.92(d, J ═ 11.8Hz, 1H), 3.15(s, 1H), 2.95(d, J ═ 2.6, 1.4Hz, 1H), 1.70H, 1H, 1.70H, 1, 2H) 0.55-0.44(m, 2H). ESI-MS M/z calculated 617.27844, Experimental 618.4(M +1)⁺(ii) a Retention time: 3.38min (LC method D).

Example 53: preparation of (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 195)

Step 1: (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1] hept-7-ylethoxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To 2-chloro-6- [3- (2-dispiro [2.0.2.1]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (5.2g, 14.45 mmol) in tetrahydrofuran (100mL) carbonyl diimidazole (2.8g, 16.51mmol) was added and the mixture was stirred at ambient temperature for 1 h. To this mixture was added a solution containing (4S) -2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino group]Propyl radical]1-methyl pyrrolidineTert-butyl ester (6.0g, 14.54mmol) in tetrahydrofuran (15 mL) followed by the addition of 1, 8-diazabicyclo [ 5.4.0%]Undec-7-ene (6.5mL, 43.47mmol) and the mixture stirred at ambient temperature for 16 h. The reaction was diluted with water (150mL) and the mixture was acidified with aqueous hydrochloric acid (15mL, 6M, 90.00 mmol). The mixture was extracted with ethyl acetate (300mL) and the organic phase was separated. The organic phase was washed with brine, dried over magnesium sulfate, filtered through celite, and concentrated in vacuo to give a white precipitate the precipitate was slurried with acetonitrile and the solid was collected by filtration using a medium pore glass frit and washed with acetonitrile the filtrate was concentrated in vacuo to give a yellow oil. The crude oil was diluted with acetonitrile and some N-methyl-2-pyrrolidone and 415g of reverse phase C was performed ₁₈Performing column chromatography, eluting with 50% -100% acetonitrile/water to obtain (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (4.5g, 41%). ESI-MS M/z calculated 753.30756, Experimental 754.4(M +1)⁺(ii) a Retention time: 3.79min (LC method D).

Step 2: 2-chloro-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] propylamino ] -2-pyridinyl ] sulfonyl ] -6- [3- (2-dispiro [2.0.2.1] hept-7-ylethoxy) pyrazol-1-yl ] pyridine-3-carboxamide (trifluoroacetate)

To (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (5.9g, 7.821 mmol) in dichloromethane (30mL) and toluene (15mL) trifluoroacetic acid (6.0mL, 77.88 mmol) was added and the mixture stirred at ambient temperature for 18 h. The solvent was removed in vacuo at a bath temperature set at 45 ℃ to give a thick yellow oil. The oil was diluted with toluene (125mL) and the solvent was removed in vacuo at a bath temperature set at 45 ℃. The oil was diluted with toluene and the solvent removed in vacuo to give a thick viscous yellow oil The isomer, 2-chloro-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl)]Propylamino group]-2-pyridyl]Sulfonyl radical]-6- [3- (2-dispiro [2.0.2.1 ]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carboxamide (trifluoroacetate) (6.0g, 100%) was used in the next step without further purification. ESI-MS M/z calculated 653.2551, Experimental 654.3 (M +1)⁺(ii) a Retention time: 2.6min (LC method B).

And step 3: (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 195)

To 2-chloro-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] group]Propylamino group]-2-pyridyl]Sulfonyl radical]-6- [3- (2-dispiro [2.0.2.1 ]]Hept-7-ylethoxy) pyrazol-1-yl]To a solution of pyridine-3-carboxamide (trifluoroacetate) (6.0g, 7.810mmol) in NMP (140mL) was added potassium carbonate (5.3g, 38.35mmol), the mixture was purged with nitrogen for 5min and then heated at 150 ℃ for 22 h. The reaction mixture was cooled to room temperature and added to water (300mL) to give an off-white solid precipitate. The mixture was carefully acidified with aqueous hydrochloric acid (12 mL, 6M, 72.00mmol) to give a multivesicular slurry, the solid was collected by filtration using a medium pore glass frit, the wet cake was dissolved in ethyl acetate (500mL) and washed with 200mL of brine, the aqueous phase was slightly cloudy and was therefore acidified with a small amount of 6N hydrochloric acid and returned to the organic phase, the aqueous phase was separated and the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to give a pale yellow oil, this crude product was diluted with acetonitrile and subjected to 415g C ₁₈Performing reverse phase column chromatography, eluting with 50% -100% acetonitrile/water, separating the product to give cream yellow foam, and vacuum drying the foam at 45 deg.C for 48 hr to obtain (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111，14.05，10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 195) (3.32g, 68%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.48(s, 1H), 8.20(d, J ═ 2.8Hz, 1H), 7.81(d, J ═ 8.2Hz, 1H), 7.57(dd, J ═ 8.5, 7.2Hz, 1H), 7.05(d, J ═ 7.1Hz, 1H), 6.97(d, J ═ 8.5Hz, 1H), 6.91(d, J ═ 8.2Hz, 1H), 6.71(d, J ═ 8.5Hz, 1H), 6.08(d, J ═ 2.7Hz, 1H), 4.21(td, J ═ 6.7, 1.3Hz, 2H), 3.92(d, J ═ 12.0Hz, 1H), 3.16(s, 1H), 2.95(d, J ═ 3.7, 1.3Hz, 2H), 3.92(d, J ═ 12.0Hz, 1H), 3.16(s, 1H), 2.95(d, J ═ 13.13, 1H), 1.7, 1.3H, 1.3H, 1H), 6.7 (s, 1H), 1H), 6.7 (m-1H), 1H), 6.3.7 (m-6.3, 1H), 1H), 1, 2H) 0.53-0.45(m, 2H). ESI-MS M/z calculated 617.27844, Experimental 618.4(M +1)⁺(ii) a Retention time: 10.29min (LC method F).

By reacting compound 195 with Ca (OCH)₃)₂、Na(OCH₃) Ca mixed with KOH to prepare Compound 195²⁺、Na⁺And K⁺Salt: 195(1g) and Ca (OCH) were mixed at room temperature₃)₂(83mg) mixed in methanol (65mL) for 30 minutes and then mixed at 65 ℃ for 30 minutes; MeOH (40mL) containing compound 195(0.6g (1mMol)) and a solution containing 25 wt% Na (OCH) were mixed at 60 deg.C₃) MeOH (250mL (1 molar equivalent)) for 20 minutes; and acetone (11mL) containing compound 195(0.6g) was mixed with 1N KOH (1 molar equivalent) at 50 ℃ for 1 hour after filtering the resulting hot solution, the filtrate was evaporated to dryness to afford the desired amorphous salt, respectively (PXRD data not shown).

Example 54: preparation of 8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 196) and 8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 197)

Step 1: 4- [2- [ [6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1] hept-7-ylethoxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridyl ] amino ] ethoxy ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- (2-dispiro [2.0.2.1]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (412mg, 1.145mmol) and carbonyldiimidazole (185.7mg, 1.145mmol) were combined in dry tetrahydrofuran (10.47mL) and stirred at 50 ℃ for 60min, then 2, 2-dimethyl-4- [2- [ (6-sulfamoyl-2-pyridyl) amino]Ethoxy radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (431.5mg, 1.041mmol) and 1, 8-diazabicyclo [5.4.0]Undec-7-ene (400.7mg, 393.6. mu.L, 2.632mmol) in tetrahydrofuran (7 mL). The reaction was heated at 50 ℃ for 4 h. The organics were separated, dried over sodium sulfate, filtered and evaporated, and then purified on silica gel using a gradient of 100% hexane to 75% ethyl acetate/hexane to give 4- [2- [ [6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1 ]) as an off-white solid]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl ]Amino group]Ethoxy radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (452mg, 57%). ESI-MS M/z calculated 755.2868, Experimental 756.41(M +1)⁺(ii) a Retention time: 0.92min (LC method A).

Step 2: 8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [173.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 188)

Reacting 4- [2- [ [6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1 ]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Ethoxy radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (410mg, 0.5421mmol) was dissolved in dichloromethane (6mL) and trifluoroacetic acid (800 μ L, 10.38mmol) was added to the mixture. The reaction solution was stirred at room temperature for 30 min. The reaction solution was concentrated in vacuo to be dried under reduced pressure to give a residue, which was then mixed with potassium carbonate (450mg, 3.256mmol), cesium fluoride (105mg, 0.6912 mmol),

Molecular sieves and dimethylsulfoxide (5mL) were combined in a vial, purged with nitrogen, capped, heated to 140 ℃ and stirred for 20 h. The reaction mixture was cooled to room temperature, filtered, and then subjected to reverse-phase preparative chromatography (over 30min, C) ₁₈Column, 30% to 99% acetonitrile (no modifier)/water (5mM hydrochloric acid)) to give 8- [3- (2- { dispiro [2.0.2.1 ] as a white solid]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 188) (330mg, 97%).¹H NMR (400 MHz, dimethylsulfoxide-d)₆)12.55(s, 1H), 8.19(d, J ═ 2.8Hz, 1H), 7.79(d, J ═ 8.2Hz, 1H), 7.59(t, J ═ 7.9Hz, 1H), 7.09(m, 2H), 6.93(d, J ═ 8.1Hz, 1H), 6.70(d, J ═ 8.5Hz, 1H), 6.08(d, J ═ 2.8Hz, 1H), 4.21(t, J ═ 6.6Hz, 2H), 4.10(s, 2H), 3.88(t, J ═ 11.8 Hz, 1H), 3.60(d, J ═ 12.4Hz, 1H), 2.86(s, 1H), 2.07(dd, J ═ 11.9, 6.0, 1H), 1.81 (d, J ═ 12.4Hz, 1H), 2.47 (dd, 1H), 2.07(dd, J ═ 11.9, 6.0, 1H), 1H, 3.8 (d, 3.8H), 3.8, 1H), 3.8 (d, 1H), 3.8, 1H), 3.8H, 1H, 5 (dd, 3.8H), 3.5H), 3.8H, 1H, 5H), 3.. ESI-MS M/z calculated 619.2577, Experimental 620.33(M +1)⁺(ii) a Retention time: 2.25min (L)C method B).

And step 3: 8- [3- (2- { dispiro [2.0.2.1 ] ]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-15-oxa-2. lambda⁶-aza-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 196) and 8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-15-oxa-2. lambda⁶-aza-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 197)

For racemic compound 8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-15-oxa-2. lambda⁶-aza-3, 9, 11, 18, 23-penta-azatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 188) (320mg, 0.5112mmol) was subjected to chiral SFC chromatography. The following SFC protocol was employed: ChiralPak AS-3 (150X 2.1mm), 3 μm; 35 ℃ mobile phase: 30% acetonitrile: methanol (90: 10), 70% carbon dioxide. The first enantiomer to be eluted was 8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl ]-12, 12-dimethyl-15-oxa-2. lambda⁶-aza-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 196) (63mg, 39%). ESI-MS M/z calculated 619.2577, Experimental 620.33(M +1)⁺(ii) a Retention time: 2.18min (LC method B) the second enantiomer to be eluted was 8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-15-oxa-2. lambda⁶-aza-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 197) (62mg, 39%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.56(s, 1H), 8.19(d, J ═ 2.8Hz, 1H), 7.79(d, J ═ 8.2Hz, 1H), 7.59(t, J ═ 7.8Hz, 1H), 7.09(d, J ═ 7.2Hz, 1H), 6.93(d, J ═ 8.2Hz, 1H), 6.70(d, J ═ 8.5Hz, 1H), 6.08(d, J ═ 2.8Hz, 1H), 4.21(t, J ═ 6.7Hz, 2H), 3.88(t, J ═ 11.9Hz, 1H), 3.60(d, J ═ 13.0Hz, 1H), 3.17(d, J ═ 4.3Hz, 3H), 2.86(s, 1H), 2.08 (s, J ═ 2.08H), 3.7 (d, J ═ 13.0Hz, 1H), 3.17(d, J ═ 4.3H, 3H), 2.86(s, 1H), 3.08 (s, 1H), 3.81, 5H), 3.7H, 3, 7H, 3.7H, 7H, 2H) 0.57-0.42(m, 2H). ESI-MS M/z calculated 619.2577, Experimental 620.33(M +1) ⁺(ii) a Retention time: 2.18min (LC method B).

Example 55: preparation of 20, 20-dimethyl-4- {3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy]-1H-pyrazol-1-yl } -10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2 (7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 1) (compound 206) and 20, 20-dimethyl-4- {3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy]-1H-pyrazol-1-yl } -10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2 (7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 207)

Step 1: 4- [3- [3- [ [ 2-chloro-6- [3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] pyrazol-1-yl ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy]Pyrazol-1-yl]Pyridine-3-carboxylic acid (350 mg, 0.9620mmol) andcarbonyldiimidazole (188mg, 1.159mmol) was combined in tetrahydrofuran (8.0mL) and stirred at room temperature for 90min, then 2, 2-dimethyl-4- [3- (3-sulfamoylpyrazol-1-yl) propyl ]Pyrrolidine-1-carboxylic acid tert-butyl ester (446mg, 1.154mmol) followed by addition of anhydrous 1, 8-diazabicyclo [5.4.0]Undec-7-ene (360 μ L, 2.407mmol) and the reaction stirred at room temperature for 30min, then heated to 40 ℃ for 20h diluting the reaction with ethyl acetate and washing with a saturated aqueous solution of sodium bicarbonate, then with brine the organics were separated, dried over sodium sulfate, evaporated and then purified by silica gel chromatography using a gradient of 100% hexane to 80% ethyl acetate/hexane followed by a second silica gel column using a gradient of 100% dichloromethane to 15% methanol/dichloromethane to give 4- [3- [3- [ [ 2-chloro-6- [3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy ] prop-hyl 1 as a white solid]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Pyrazol-1-yl]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (360mg, 51%). ESI-MS M/z calculated 731.3232, Experimental 732.5(M +1)⁺(ii) a Retention time: 2.14min (LC method G).

Step 2: 20, 20-dimethyl-4- {3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy]-1H-pyrazol-1-yl } -10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7 ]Docosac-2 (7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (Compound 198)

4- [3- [3- [ [ 2-chloro-6- [3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Pyrazol-1-yl]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (360mg, 0.4916 mmol), potassium carbonate (400mg, 2.894mmol),

Molecular sieves and NMP (10mL) were added to a 20mL microwave vial, purged with nitrogen, capped, heated to 160 ℃, and stirred for 96hThe organics were separated, dried over sodium sulfate, evaporated, and then purified by silica gel chromatography using a gradient of 100% hexane to 90% ethyl acetate/hexane to give 20, 20-dimethyl-4- {3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy ] hexane as a white solid]-1H-pyrazol-1-yl } -10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosae-2 (7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (compound 198) (59.7mg, 20%).¹H NMR (400MHz, chloroform-d) 8.42(s, 1H), 8.17(d, J ═ 2.8Hz, 1H), 7.68(d, J ═ 8.2Hz, 1H), 7.48(d, J ═ 2.3Hz, 1H), 7.07(d, J ═ 2.3Hz, 1H), 7.03(d, J ═ 8.3Hz, 1H), 5.88(d, J ═ 2.7Hz, 1H), 4.43-4.29(m, 1H), 4.24(t, J ═ 7.2Hz, 2H), 4.00-3.87(m, 1H), 2.75(t, J ═ 8.3Hz, 1H), 2.16-2.12(m, 1H), 2.03-1.94 (m, 2H), 1.76(q, 7.7, 1H), 7.75 (t, J ═ 8.3Hz, 1H), 2.16-2.12(m, 1H), 2.03-1H), 2.94 (m, 1H), 7.7, 7.7.7, 1H, 6H, 1H, 7.7.7H, 1H, 6H, 7.7H, 1H, 6H, 15H, 7H, 1, 1H) ESI-MS calculated M/z 595.29407, Experimental 596.2(M +1) ⁺(ii) a Retention time: 1.94min (LC method E).

And step 3: 20, 20-dimethyl-4- {3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy]-1H-pyrazol-1-yl } -10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2 (7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 1) (compound 206) and 20, 20-dimethyl-4- {3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy]-1H-pyrazol-1-yl } -10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2 (7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 207)

Chromatography by chiral SFC using ChiralPak AS-H (250X 21.2)mm column, 5 μm particle size) and 32% acetonitrile to methanol (90: 10; modifier-free)/68% carbon dioxide mobile phase (0.5mL/min) to racemic 20, 20-dimethyl-4- {3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy]-1H-pyrazol-1-yl } -10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Dodecan-2 (7), 3, 5, 11(22), 12-pentaen-8, 10, 10-trione (compound 198) (45.4mg, 0.07544mmol) was isolated to give 20, 20-dimethyl-4- {3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy ] as a white solid of the first enantiomer to be eluted ]-1H-pyrazol-1-yl } -10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2 (7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 1) (compound 206) (18.9 mg, 84%). ESI-MS M/z calculated 595.29407, Experimental 596.2(M +1)^+；Retention time: 1.94 min (LC method E.) the second enantiomer to be eluted was 20, 20-dimethyl-4- {3- [2- (2, 2, 3, 3-tetramethylcyclopropyl) ethoxy]-1H-pyrazol-1-yl } -10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2 (7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 207) (19.2mg, 85%).¹H NMR (400MHz, chloroform-d) 8.38(s, 1H), 8.17(d, J ═ 2.8Hz, 1H), 7.68(d, J ═ 8.3Hz, 1H), 7.48(d, J ═ 2.3Hz, 1H), 7.12-6.99(M, 2H), 5.88(d, J ═ 2.7Hz, 1H), 4.43-4.30(M, 1H), 4.24(t, J ═ 7.2Hz, 2H), 3.93(t, J ═ 12.1Hz, 1H), 2.74(t, J ═ 8.2Hz, 1H), 2.17-2.11(M, 1H), 2.04-1.96(M, 2H), 1.76(q, J ═ 7.2, 3H), 1.59(s, 6H), 1.7, 0.7H, 19 (M, 1H), 5.19 (M, 2H), 5.5H, 13 (M, 15H), 5 (M, 2H, 13H), 5 (M, 13H, 13 (M, 15H), 5H), 1H, 13 (q, 5, 3H, 1H, 0, 15H), 5H). ⁺(ii) a Retention time: 1.94min (LC method E).

Example 56: preparation of (14S) -12, 12-dimethyl-8- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl]-2λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (22), 5, 7, 9, 19(23), 20-hexaene-2, 24-triones (Compound 208)

Step 1: 3, 3, 3-trifluoro-2, 2-dimethyl-propan-1-ol

A1L 3-neck round bottom flask was equipped with a mechanical stirrer, cooling bath, addition funnel and J-Kem temperature probe. The vessel was charged with lithium aluminum hydride pellets (6.3g, 0.1665mol) under a nitrogen atmosphere. The vessel was then charged with tetrahydrofuran (200mL) under a nitrogen atmosphere the mixture was stirred at room temperature for 0.5h to dissolve the pellets. The cooling bath was then charged with water containing crushed ice and the reaction temperature was lowered to 0 ℃. The addition funnel was charged with a solution of 3, 3, 3-trifluoro-2, 2-dimethyl-propionic acid (20g, 0.1281mol) in tetrahydrofuran (60mL) and the clear pale yellow solution was added dropwise over 1h after the addition was complete, the mixture was slowly warmed to room temperature and stirring was continued for 24h the suspension was cooled to 0 ℃ using an ice bath and then quenched by very slow and dropwise addition of water (6.3 mL), followed by addition of sodium hydroxide solution (15 wt.; 6.3mL) and then finally water (18.9mL), the reaction temperature of the resulting white suspension was recorded as 5 ℃, the suspension was stirred at about 5 ℃ for 30min and then filtered through a 20mm celite pad. The filter cake was washed with tetrahydrofuran (2X 100 mL.) the filtrate was dried over sodium sulfate (150g) and then filtered the filtrate was concentrated under reduced pressure to provide a mixture containing the

product

3, 3, 3-trifluoro-2, 2-dimethyl-propan-1-ol in tetrahydrofuran (73 wt% of the product (10.95g) and 27 wt% tetrahydrofuran, as by ¹H-NMR determined) was obtained.15 g of a clear colorless oil the distillate from the rotary evaporation was distilled using a 30cm vilago column at atmospheric pressure to provide 8.75g of a residue containing 60% by weight of tetrahydrofuran and 40% by weight of the product (3.5 g.) these mixtures of products in tetrahydrofuran were combined to give 3, 3, 3-trifluoro-2, 2-dimethyl-propan-1-ol (14.45 g)61 wt% in tetrahydrofuran, 79% yield).¹H NMR (400MHz, dimethylsulfoxide-d)₆)4.99(t，J＝5.7Hz，1H)，3.38(dd，J＝5.8， 0.9Hz，2H)，1.04(d，J＝0.9Hz，6H).

Step 2: 3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) pyrazole-1-carboxylic acid tert-butyl ester

A mixture of 3, 3, 3-trifluoro-2, 2-dimethyl-propan-1-ol (10g, 70.36mmol) and tert-butyl 3-hydroxypyrazole-1-carboxylate (12.96g, 70.36mmol) in toluene (130mL) was treated with triphenylphosphine (20.30g, 77.40 mmol) followed by isopropyl N-isopropoxycarbonyliminocarbamate (14.99mL, 77.40 mmol) and the mixture was stirred at 110 ℃ for 16 h. The yellow solution was concentrated under reduced pressure, diluted with heptane (100mL) and the precipitated triphenylphosphine oxide was removed by filtration and washed with heptane/toluene 4: 1(100 mL). The yellow filtrate was evaporated and the residue was purified by silica gel chromatography with a linear gradient of ethyl acetate/hexane (0-40%) to give tert-butyl 3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) pyrazole-1-carboxylate (12.3g, 57%) as an off-white solid. ¹H NMR (400MHz, dimethylsulfoxide-d)₆)8.10(d, J ═ 3.0Hz, 1H), 6.15(d, J ═ 3.0Hz, 1H), 4.18(s, 2H), 1.55(s, 9H), 1.21(s, 6H). ESI-MS M/z calculated 308.13477, Experimental 309.0(M +1)⁺(ii) a Retention time: 1.92min (LC method B).

And step 3: 3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) -1H-pyrazole

Tert-butyl 3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) pyrazole-1-carboxylate (13.5g, 43.79mmol) was treated with 4M hydrogen chloride in dioxane (54.75mL, 219.0mmol) and the mixture was stirred at 45 ℃ for 1h the reaction mixture was evaporated to dryness and the residue was treated with 1M sodium hydroxideAqueous solution (100mL) and methyl tert-butyl ether (100mL), washed with brine (50mL) and extracted with methyl tert-butyl ether (50mL) the combined organic phases were dried over sodium sulfate, filtered and evaporated to give 3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) -1H-pyrazole as an off-white waxy solid (9.0g, 96%).¹H NMR (400MHz, dimethylsulfoxide-d)₆) 11.91(s, 1H), 7.52(d, J ═ 2.2Hz, 1H), 5.69(t, J ═ 2.3Hz, 1H), 4.06(s, 2H), 1.19(s, 6H), ESI-MS M/z calculated 208.08235, experimental 209.0(M +1)⁺(ii) a Retention time: 1.22min (LC method B).

And 4, step 4: 2-chloro-6- [3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) pyrazol-1-yl ] pyridine-3-carboxylic acid tert-butyl ester

To a solution of tert-butyl 2, 6-dichloropyridine-3-carboxylate (10.4g, 41.9mmol) and 3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) -1H-pyrazole (9.0g, 41.93mmol) in N, N-dimethylformamide (110mL) were added potassium carbonate (7.53g, 54.5mmol) and 1, 4-diazabicyclo [2.2.2 ]]Octane (706mg, 6.29mmol) and the mixture stirred at room temperature for 16 h. The milky suspension was cooled in a cold water bath and cold water (130 mL) was slowly added. The thick suspension was stirred at room temperature for 1h, filtered and washed with water to give 2-chloro-6- [3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) pyrazol-1-yl as an off-white solid after drying in vacuo]Pyridine-3-carboxylic acid tert-butyl ester (17.6g, 99%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)8.44(d, J ═ 2.9Hz, 1H), 8.31(d, J ═ 8.4Hz, 1H), 7.76(d, J ═ 8.4Hz, 1H), 6.26(d, J ═ 2.9Hz, 1H), 4.27(s, 2H), 1.57(s, 9H), 1.24(s, 6H). ESI-MS M/z calculated 419.12234, Experimental 420.0 (M +1)⁺(ii) a Retention time: 2.36min (LC method B).

And 5: 2-chloro-6- [3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) pyrazol-1-yl ] pyridine-3-carboxylic acid

Reacting 2-chloro-6- [3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (17.6g, 40.25mmol) is suspended in isopropanol (85mL), treated with hydrochloric acid (34mL, 6M, 201mmol) and heated to reflux for 3h (almost completely into solution and start precipitating again at reflux), the suspension is diluted with water (51mL) at reflux and allowed to cool to room temperature with stirring for 2.5h the solid is collected by filtration, washed with isopropanol/water 1: 1(50mL), additional water and dried overnight in a dry box under vacuum at 45-50 ℃ with nitrogen bleed to give 2-chloro-6- [3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) pyrazol-1-yl as an off-white solid]Pyridine-3-carboxylic acid (13.7g, 91%).¹H NMR (400MHz, dimethylsulfoxide-d)₆) 13.61(s, 1H), 8.44(d, J ═ 2.9Hz, 1H), 8.39(d, J ═ 8.4Hz, 1H), 7.77(d, J ═ 8.4Hz, 1H), 6.25(d, J ═ 2.9Hz, 1H), 4.28(s, 2H), 1.24(s, 6H) ESI-MS M/z calculated value 363.05975, experimental value 364.0(M +1)⁺(ii) a Retention time: 1.79min (LC method B).

Step 6: (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (174.5 mg, 0.4702mmol) and carbonyldiimidazole (95.31mg, 0.5878mmol) were combined in tetrahydrofuran (2.223 mL) and stirred at room temperature for 90 min. Subsequently, (4S) -2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino group was added in the form of a solution in tetrahydrofuran (855. mu.L)]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (194mg, 0.4702mmol) was added followed by 1, 8-diazabicyclo [5.4.0]Undec-7-ene (357.9mg, 2.351 mmol) and the reaction stirred at 50 ℃ for 2.5 h. Stirring was continued at room temperature for 4 daysThe reaction was then diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution followed by brine. The organics were separated, dried over sodium sulfate, evaporated, and then purified by silica gel chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate to give the pure product material, and the fractions were mixed with the starting material acid₁₈(2) Column (75 × 30mM, 5 μm particle size) (pn: 00C-4252-U0-AX) and two gradient runs of 30-99% mobile phase B over 15.0min (mobile phase a ═ water (5mM hydrochloric acid), mobile phase B ═ acetonitrile, flow rate ═ 50mL/min, injection volume ═ 950 μ L and column temperature ═ 25 ℃) were purified and the pure product fractions were combined with the pure material from the original silica column to give (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) pyrazol-1-yl as a white solid ]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (110.4mg, 31%). ESI-MS M/z calculated 757.2636, Experimental 758.4(M +1)⁺(ii) a Retention time: 0.9min (LC method A).

And 7: 2-chloro-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] propylamino ] -2-pyridinyl ] sulfonyl ] -6- [3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) pyrazol-1-yl ] pyridine-3-carboxamide

To a solution containing (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (110.4mg, 0.1456mmol) in a round bottom flask was added dichloromethane (2mL) and trifluoroacetic acid (450 μ L, 5.841mmol) after 1h at rt the reaction was evaporated to dryness. The crude reaction mixture was neutralized with saturated sodium bicarbonate and extracted with ethyl acetate. The product appeared and very little methanol was used to aid extraction. The organic layer was separated and evaporated to provide 2-chloro-N- [ [6- [3-[ (3S) -5, 5-dimethylpyrrolidin-3-yl]Propylamino group]-2-pyridyl]Sulfonyl radical]-6- [3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) pyrazol-1-yl ]Pyridine-3-carboxamide (95mg, 99%). ESI-MS M/z calculated 657.2112, Experimental 658.4(M +1)⁺(ii) a Retention time: 1.62min (LC method B).

And 8: (14S) -12, 12-dimethyl-8- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl]-2λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 208)

To a vial was added cesium fluoride (33.5mg, 0.2205mmol), potassium carbonate (100mg, 0.7236mmol), and,

Molecular sieves and 2-chloro-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] radical]Propylamino group]-2-pyridyl]Sulfonyl radical]-6- [3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) pyrazol-1-yl]A solution of pyridine-3-carboxamide (95mg, 0.1443mmol) in dimethylsulfoxide (2.5mL) the reaction was capped and placed in a preheated 150 ℃ oil bath overnight. The reaction was cooled to room temperature, filtered and purified by HPLC (30% -99% acetonitrile: water + 0.1% hydrochloric acid modifier) to give (14S) -12, 12-dimethyl-8- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl as a tan solid]-2λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 208) (45.5mg, 51%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.49(s，1H)，8.23(d，J＝2.8 Hz，1H)，7.82(d，J＝8.2Hz，1H)，7.58(dd，J＝8.5，7.2Hz，1H)，7.05(d，J＝7.1Hz， 1H)，6.95(d，J＝8.2Hz，2H)，6.71(d，J＝8.5Hz，1H)，6.18(d，J＝2.7Hz，1H)，4.27- 4.19(m，2H)，3.92(d，J＝12.4Hz，1H)，3.16(s1H), 2.95(d, J ═ 13.5Hz, 1H), 2.71(t, J ═ 10.8Hz, 1H), 2.13(s, 1H), 1.86(dd, J ═ 11.8, 5.2Hz, 1H), 1.77(s, 1H), 1.65-1.48 (M, 9H), 1.35(dd, J ═ 25.8, 14.3Hz, 1H), 1.24(s, 6H), ESI-MS M/z calculated value 621.2345, experimental value 622.3(M +1)⁺(ii) a Retention time: 2.24min (LC method B).

Example 57: preparation of (14S) -12, 12-dimethyl-8- [3- (4, 4, 4-trifluoro-3, 3-dimethylbutoxy) -1H-pyrazol-1-yl]-2λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 212)

Step 1: (3, 3, 3-trifluoro-2, 2-dimethyl-propyl) methanesulfonate

To a solution of 3, 3, 3-trifluoro-2, 2-dimethyl-propan-1-ol (17g, 104.1mmol) in anhydrous dichloromethane (150mL) was added triethylamine (45.0mL, 322.9 mmol.) the reaction was cooled to 0 ℃ and methanesulfonyl chloride (10mL, 129.2mmol) was added slowly dropwise under a nitrogen atmosphere. The resulting heterogeneous mixture was stirred for 1h while warming to ambient temperature. The reaction was then quenched with cold water (150mL) and extracted twice with dichloromethane (200mL) the organic layer was dried over sodium sulfate, filtered and evaporated (bath temperature 20 ℃ at 300 mbar) to afford 3, 3, 3-trifluoro-2, 2-dimethyl-propyl methanesulfonate (18.4g, 80%) as a clear yellowish liquid. ¹H NMR (400MHz, chloroform-d) 4.13(d, J ═ 2.4Hz, 2H), 3.03(d, J ═ 2.4Hz, 3H), 1.21(d, J ═ 2.4Hz, 6H).

Step 2: 4, 4, 4-trifluoro-3, 3-dimethyl-butyronitrile

To a solution of (3, 3, 3-trifluoro-2, 2-dimethyl-propyl) methanesulfonate (30.00g, 136.2mmol) in dimethyl sulfoxide (150mL) was added sodium cyanide (20.05g, 409.1 mmol.) the reaction was equipped with a reflux condenser and heated at 120 ℃ for 3 days, then the reaction was cooled to 0 ℃ and ice water was added followed by brine. The reaction mixture was then extracted twice with ether, the organic layers were combined and dried over sodium sulfate, filtered and evaporated to give 4, 4, 4-trifluoro-3, 3-dimethyl-butyronitrile (18.43g, 90%) as an orange liquid.¹H NMR (400MHz, chloroform-d) 2.56(s, 2H), 1.33(s, 6H).

And step 3: 4, 4, 4-trifluoro-3, 3-dimethyl-butyric acid

To a solution of 4, 4, 4-trifluoro-3, 3-dimethyl-butyronitrile (12g, 39.70mmol) in ethanol (100mL) was added sodium hydroxide (35mL, 6M, 210.0mmol) and the resulting clear amber solution was heated to 70 ℃ overnight. The reaction mixture was cooled to ambient temperature and water (30mL) was added to the reaction mixture and extracted with ether the ether layer was washed with 6M sodium hydroxide. The aqueous layers were combined and the aqueous solution was carefully adjusted to pH 1 with concentrated hydrochloric acid at 0 ℃ followed by extraction of the mixture with ether (3 × 100 mL.) the organic extracts were combined and dried over sodium sulfate, filtered and concentrated (at 300mbar, bath temperature 20 ℃) to give 4, 4, 4-trifluoro-3, 3-dimethyl-butyric acid (3.8g, 28%). ¹H NMR (400MHz, chloroform-d) 2.48(s, 2H), 1.27-1.26(s, 6H).

And 4, step 4: 4, 4, 4-trifluoro-3, 3-dimethyl-butan-1-ol

To a slurry of lithium aluminum hydride (438mg, 11.24mmol) in ether (30 mL) at 0 deg.C under nitrogen via an addition funnelA solution of 4, 4, 4-trifluoro-3, 3-dimethyl-butyric acid (3.8g, 11.17mmol) in ether (30 mL) was added dropwise. The resulting slurry was stirred at ambient temperature for 24 h. The reaction mixture was cooled in an ice bath and quenched sequentially with water (450 μ L, 24.98mmol) (slowly), then sodium hydroxide (450 μ L, 6M, 2.700 mmol), then water (1.35mL, 74.94mmol) to give a white granular slurry which was further stirred with anhydrous magnesium sulfate for 30min, then filtered through celite. The precipitate was washed with ether and the filtrate was concentrated (at about 400mbar and 20 ℃ water bath) to give 4, 4, 4-trifluoro-3, 3-dimethyl-butan-1-ol (1.5g, 86%) as a colourless liquid.¹H NMR (400MHz, chloroform-d) 3.77(td, J ═ 7.3, 0.8Hz, 2H), 1.79(t, J ═ 7.4Hz, 2H), 1.15(d, J ═ 0.8Hz, 6H).

And 5: 3- (4, 4, 4-trifluoro-3, 3-dimethyl-butoxy) pyrazole-1-carboxylic acid tert-butyl ester

A solution of 4, 4, 4-trifluoro-3, 3-dimethyl-butan-1-ol (1.0g, 6.404mmol), 3-hydroxypyrazole-1-carboxylic acid tert-butyl ester (1.2g, 6.515mmol), triphenylphosphine (1.9g, 7.244mmol) in anhydrous tetrahydrofuran (10mL) was cooled in an ice bath and DIAD (1.5mL, 7.618mmol) was added slowly under a nitrogen atmosphere. The reaction was slowly warmed to room temperature and stirred overnight the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, then brine, and dried over sodium sulfate, filtered and evaporated in vacuo the residue was purified by silica gel column chromatography using a gradient of 100% hexane to 50% ethyl acetate/hexane to give tert-butyl 3- (4, 4, 4-trifluoro-3, 3-dimethyl-butoxy) pyrazole-1-carboxylate (650mg, 31%) as a colorless oil. ¹H NMR (400MHz, chloroform-d) 7.83(d, J ═ 2.9Hz, 1H), 5.84(d, J ═ 3.1Hz, 1H), 4.38(t, J ═ 7.2Hz, 2H), 1.98(t, J ═ 7.1Hz, 2H), 1.61(s, 9H), 1.18(s, 6H), ESI-MS M/z calculated 322.15042, experimental 323.18(M +1)⁺(ii) a Retention time: 0.74min (LC method A).

Step 6: 3- (4, 4, 4-trifluoro-3, 3-dimethyl-butoxy) -1H-pyrazole

A solution of tert-butyl 3- (4, 4, 4-trifluoro-3, 3-dimethyl-butoxy) pyrazole-1-carboxylate (650mg, 2.017 mmol) and trifluoroacetic acid (1mL, 12.98mmol) in dichloromethane (4mL) was stirred at room temperature for 4h. The combined extracts were dried over sodium sulfate, filtered and evaporated to give 3- (4, 4, 4-trifluoro-3, 3-dimethyl-butoxy) -1H-pyrazole (448mg, 100%) as a colourless oil, calculated ESI-MS M/z 222.09799, experimental 223.09(M +1)⁺(ii) a Retention time: 0.53min (LC method A).

And 7: 2-chloro-6- [3- (4, 4, 4-trifluoro-3, 3-dimethyl-butoxy) pyrazol-1-yl ] pyridine-3-carboxylic acid tert-butyl ester

3- (4, 4, 4-trifluoro-3, 3-dimethyl-butoxy) -1H-pyrazole (448mg, 2.016mmol), tert-butyl 2, 6-dichloropyridine-3-carboxylate (501mg, 2.019mmol), potassium carbonate (336mg, 2.431mmol) and 1, 4-diazabicyclo [2.2.2 mmol) were reacted at room temperature ]A mixture of octane (46mg, 0.4101mmol) in dimethylsulfoxide (5mL) was stirred for 15 h. The reaction was diluted with water and extracted with ethyl acetate the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated the residue was purified by silica gel column chromatography using a gradient of 100% hexane to 20% ethyl acetate/hexane to give 2-chloro-6- [3- (4, 4, 4-trifluoro-3, 3-dimethyl-butoxy) pyrazol-1-yl as a white solid]Pyridine-3-carboxylic acid tert-butyl ester (471mg, 54%).¹H NMR (400MHz, chloroform-d) 8.36(d, J ═ 2.8Hz, 1H), 8.19(dd, J ═ 8.2, 1.8Hz, 1H), 7.69(dd, J ═ 8.2, 1.8Hz, 1H), 5.94(d, J ═ 2.8Hz, 1H), 4.38(t, J ═ 7.2Hz, 2H), 2.03(t,j ═ 7.2Hz, 2H), 1.62(d, J ═ 2.1Hz, 9H), 1.22(s, 6H), ESI-MS M/z calculated 433.138, experimental 434.2 (M +1)⁺(ii) a Retention time: 0.91min (LC method A).

And 8: (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (4, 4, 4-trifluoro-3, 3-dimethyl-butoxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

Tert-butyl-2-chloro-6- [3- (4, 4, 4-trifluoro-3, 3-dimethyl-butoxy) pyrazol-1-yl at room temperature ]A solution of pyridine-3-carboxylate (150mg, 0.3457mmol) in trifluoroacetic acid (150. mu.L, 1.947mmol) and dichloromethane (1mL) was stirred for 2 h. The solvent was removed and the residue was dried under high vacuum to give a white solid. To a solution of this solid in tetrahydrofuran (2mL) was added carbonyldiimidazole (68mg, 0.4194mmol) and the reaction mixture was stirred at room temperature for 4 h. Subsequently, (4S) -2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino group is added]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (146mg, 0.3539mmol) in tetrahydrofuran (2mL) followed by the addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (110 μ L, 0.7356mmol) and the reaction stirred for 16h the reaction was diluted with ethyl acetate and washed with a mixture of saturated ammonium chloride and brine (1: 1). The organics were separated, dried over sodium sulfate, filtered and evaporated the resulting brown residue was purified by silica gel chromatography using a gentle gradient of 100% dichloromethane to 20% methanol/dichloromethane to give (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (4, 4, 4-trifluoro-3, 3-dimethyl-butoxy) pyrazol-1-yl as a white solid]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (82mg, 31%). ESI-MS M/z calculated 771.27924, Experimental 772.36(M +1) ⁺(ii) a Retention time: 0.89min (LC method A).

And step 9: (14S) -12, 12-dimethyl-8- [3- (4, 4, 4-trifluoro-3, 3-dimethylbutoxy) -1H-pyrazol-1-yl]-2λ⁶-a sulfur-3-group of compounds,9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 212)

(4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (4, 4, 4-trifluoro-3, 3-dimethyl-butoxy) pyrazol-1-yl at room temperature]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]A solution of tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (82mg, 0.1062mmol) in dichloromethane (500. mu.L) and trifluoroacetic acid (100. mu.L, 1.307mmol) was stirred for 4 h. The solvent was then removed and the residue was dried in vacuo. The residue was dissolved in dimethyl sulfoxide (5mL) and oven dried

Molecular sieves, and the reaction mixture was stirred for 10 min. Subsequently, cesium fluoride (51mg, 0.3357mmol) and potassium carbonate (48mg, 0.3473mmol) were added, and the reaction mixture was heated at 130 ℃ overnight. The reaction mixture was filtered through Whatman filter disc (puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS method using a double gradient run of 50-99% mobile phase B over 15.0min (mobile phase a ═ water (0.05% hydrochloric acid), mobile phase B ═ acetonitrile) to give (14S) -12, 12-dimethyl-8- [3- (4, 4, 4-trifluoro-3, 3-dimethylbutoxy) -1H-pyrazol-1-yl as a white solid ]-2λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 212) (34.5mg, 51%).¹H NMR (400MHz, chloroform-d) 9.84(s, 1H), 8.20(d, J ═ 2.8Hz, 1H), 8.07(d, J ═ 8.4Hz, 1H), 7.54(dt, J ═ 15.1, 7.2Hz, 2H), 7.27(d, J ═ 8.3Hz, 1H), 6.57(d, J ═ 8.1Hz, 1H), 5.91(d, J ═ 2.8Hz, 1H), 4.38(t, J ═ 7.2Hz, 2H), 3.91(s, 1H), 3.41-3.31(m, 1H), 3.17(d, J ═ 14.5Hz, 1H), 3.06(t, J ═ 9.7Hz, 1H), 2.62(s, 1H), 2.09 (t, J ═ 9.7Hz, 1H), 3.09 (J ═ 2H), 3.7H, 1H), 3.11H, 7J ═ 2.9, 11H, 1H, 7H, 1H, 7J ═ 2H, 1H, 7H, 1H, 7H1.22(d, J ═ 0.8Hz, 6H). ESI-MS M/z calculated 635.2502, Experimental 636.2 (M +1)⁺(ii) a Retention time: 1.14min (LC method J).

Example 58: preparation of 8- [3- (3, 3-dimethylbutyl) -2-oxoimidazolidin-1-yl]-12, 12, 17-trimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer pair 1) (compound 209), 8- [3- (3, 3-dimethylbutyl) -2-oxoimidazolidin-1-yl ]-12, 12, 17-trimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer pair 2) (compound 210), 8- [3- (3, 3-dimethylbutyl) -2-oxoimidazolidin-1-yl]-12, 12, 17-trimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer pair 1, enantiomer 1) (compound 215), 8- [3- (3, 3-dimethylbutyl) -2-oxoimidazolidin-1-yl]-12, 12, 17-trimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer pair 1, enantiomer 2) (compound 216), 8- [3- (3, 3-dimethylbutyl) -2-oxoimidazolidin-1-yl]-12, 12, 17-trimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer pair 2, enantiomer 1) (compound 218) and 8- [3- (3, 3-dimethylbutyl) -2-oxoimidazolidin-1-yl ]-12, 12, 17-trimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer pair 2, enantiomer 2) (compound 219)

Step 1: n- [2- (3, 3-dimethylbutylamino) ethyl ] carbamic acid tert-butyl ester

To a solution of tert-butyl N- (2-aminoethyl) carbamate (25g, 156.04mmol) in methanol (400mL) was added 3, 3-dimethylbutyraldehyde (20mL, 159.35mmol) and the mixture was stirred at room temperature for 1 h. Cool to 0 ℃ and slowly add sodium borohydride (6.2g, 163.88 mmol.) stir the resulting mixture at room temperature for 16 h. The reaction was concentrated, and the residue was then redissolved in ethyl acetate (500 mL). The resulting solution was washed twice with a saturated aqueous solution of sodium hydrogencarbonate (2X 300mL) and brine (1X 500mL), followed by drying over sodium sulfate. The solution was filtered and concentrated to give N- [2- (3, 3-dimethylbutylamino) ethyl ] ethyl as an oil]Tert-butyl carbamate (37.5g, 96%). ESI-MS M/z calculated 244.37, Experimental 245.5(M +1)⁺(ii) a Retention time: 2.25 min (LC method P).

Step 2: 1- (3, 3-dimethylbutyl) imidazolidin-2-one

To a 1000mL flask was added N- [2- (3, 3-dimethylbutylamino) ethyl ] ethyl ]Tert-butyl carbamate (15.8 g, 64.65mmol) to tetrahydrofuran (200mL) was added solid potassium tert-butoxide (21.77g, 194.0mmol) and the resulting yellow solution was heated to 60 ℃ for 3h, the mixture was cooled to ambient temperature and acidified to pH 1-2 with aqueous hydrochloric acid (1M) and concentrated under reduced pressure the aqueous residue was extracted with ethyl acetate (2 × 200mL), the organic phase was washed twice with brine (100mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a beige solid which was purified by silica gel flash column chromatography (0% to 10% methanol/ethyl acetate) to give 1- (3, 3-dimethylbutyl) imidazolidin-2-one (8.3g, 72%) as a white solid.¹H NMR (300MHz, dimethylsulfoxide-d)₆) ppm of 0.89(s, 9H), 1.26-1.37(m, 2H), 2.97-3.09(m, 2H), 3.14-3.22(m, 2H), 3.24-3.32(m, 2H), 6.12-6.32(m, 1H). ESI-MS M/z calculated 170.252, Experimental 171.2(M +1)⁺(ii) a Retention time: 2.17min (LC method H).

And step 3: 4- [3- [ [6- [ (2, 6-dichloropyridine-3-carbonyl) sulfamoyl ] -2-pyridyl ] amino ] butyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

A100 mL round-bottomed flask purged with nitrogen was charged with 2, 6-dichloropyridine-3-carboxylic acid (220 mg, 1.146mmol), carbonyldiimidazole (185mg, 1.141mmol), and anhydrous tetrahydrofuran (7mL) under nitrogen, the mixture was stirred at room temperature under nitrogen for 1h, in a separate 100mL flask, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino was prepared under nitrogen ]Butyl radical]A solution of pyrrolidine-1-carboxylic acid tert-butyl ester (485mg, 1.137mmol) in anhydrous tetrahydrofuran (3mL) and was then added to the activated ester solution by syringe. Addition of 1, 8-diazabicyclo [5.4.0 ] via syringe]Undec-7-ene (373 μ L, 2.494 mmol) and the reaction mixture was stirred at room temperature under nitrogen atmosphere for 6h. The two phases were separated. The aqueous phase was extracted with ethyl acetate (30 mL.) the combined organic extracts were washed with brine (30mL) and dried over sodium sulfate. After filtration and evaporation of the solvent, the residue was dissolved in dichloromethane and purified by silica gel chromatography using a gradient of ethyl acetate (0% to 100% over 30 min)/hexane to give 4- [3- [ [6- [ (2, 6-dichloropyridine-3-carbonyl) sulfamoyl as a mixture of white solid foams of diastereomers]-2-pyridyl]Amino group]Butyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (412mg, 60%). ESI-MS calculated M/z 599.1736, Experimental 600.21 (M +1)⁺(ii) a Retention time: 0.77min (LC method A).

And 4, step 4: 8-chloro-12, 12, 17-trimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 1 4.05，10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione

4- [3- [ [6- [ (2, 6-dichloropyridine-3-carbonyl) sulfamoyl group at room temperature]-2-pyridyl]Amino group]Butyl radical]A solution of tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (412mg, 0.6860mmol) in dichloromethane (4mL) and trifluoroacetic acid (0.55mL, 7.187mmol) was stirred for 4 h. The solvent was removed and the residue was dissolved in ethyl acetate (100mL), the solution was then washed with a saturated solution of sodium bicarbonate and water, the organic extract was concentrated and dried in vacuo, the resulting residue was dissolved in dimethyl sulfoxide (3mL), and added

Molecular sieves and stirring the reaction mixture for 10min then cesium fluoride (312.5mg, 2.057mmol) and potassium carbonate (288.4mg, 2.087mmol) were added and the reaction mixture was heated at 140 ℃ overnight. The reaction mixture was filtered and water was added to the filtrate, the solution was extracted with ethyl acetate, and the organic extract was washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting brown residue was purified by column chromatography on silica gel using a gradient from 100% dichloromethane to 50% dichloromethane/methanol to give 8-chloro-12, 12, 17-trimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (98mg, 31%). ESI-MS M/z calculated 463.1445, Experimental 464.19(M +1)⁺(ii) a Retention time: 0.74min (LC method A).

And 5: 8- [3- (3, 3-dimethylbutyl) -2-oxoimidazolidin-1-yl radical]-12, 12, 17-trimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer pair 1) (compound 209) and 8- [3- (3, 3-dimethylbutyl) -2-oxoimidazolidin-1-yl]-12, 12, 17-trimethyl-2 λ⁶-thia-3, 911, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer pair 2) (compound 210)

A4 mL vial was charged with 8-chloro-12, 12, 17-trimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (89mg, 0.1918mmol), 1- (3, 3-dimethylbutyl) imidazolidin-2-one (46mg, 0.2702mmol), Pd₂(dba)₃(46mg, 0.05023mmol), Xantphos (29mg, 0.05012mmol), cesium carbonate (314mg, 0.9637 mmol) and anhydrous dioxane (3mL). the mixture was sparged with nitrogen for 1-2min, capped and stirred at 120 ℃ for 14 h. The solvent was evaporated, the reaction was diluted with dimethyl sulfoxide (900 μ L), microfiltered and subjected to reverse phase preparative HPLC (C) using a gradient of acetonitrile in water (1 to 99% over 15min) and hydrochloric acid as modifier ₁₈) To give 8- [3- (3, 3-dimethylbutyl) -2-oxoimidazolidin-1-yl as the first diastereomer pair to be eluted]-12, 12, 17-trimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer pair 1) (compound 209) (34mg, 59%); ESI-MS M/z calculated 597.30975, Experimental 598.36(M +1)⁺(ii) a Retention time: 2.04min (LC method B); and 8- [3- (3, 3-dimethylbutyl) -2-oxoimidazolidin-1-yl as a second diastereomer pair to be eluted]-12, 12, 17-trimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer pair 2) (compound 210) (63.5mg, quant.); ESI-MS M/z calculated 597.30975, Experimental 598.36(M +1)⁺(ii) a Retention time: 2.07min (LC method B).

Step 6: 8- [3- (3, 3-dimethylbutyl)-2-oxoimidazolidin-1-yl radical]-12, 12, 17-trimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer pair 1, enantiomer 1) (compound 215) and 8- [3- (3, 3-dimethylbutyl) -2-oxoimidazolidin-1-yl ]-12, 12, 17-trimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer pair 1, enantiomer 2) (compound 216)

P-8- [3- (3, 3-dimethylbutyl) -2-oxoimidazolidin-1-yl]-12, 12, 17-trimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer pair 1) (compound 209) (31mg, 0.05134mmol) was subjected to chiral SFC chromatography using the following SFC scheme: ChiralPak AS-3 (150X 2.1mm), 3 μm; 35 ℃ mobile phase: 30% acetonitrile: methanol (90: 10), 70% carbon dioxide. The first enantiomer to be eluted is 8- [3- (3, 3-dimethylbutyl) -2-oxoimidazolidin-1-yl]-12, 12, 17-trimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer pair 1, enantiomer 1) (compound 215) (8.1mg, 52%). ESI-MS M/z calculated 597.30975, Experimental 598.1(M +1) ⁺(ii) a Retention time: 2.06min (LC method B). The second enantiomer to be eluted is 8- [3- (3, 3-dimethylbutyl) -2-oxoimidazolidin-1-yl]-12, 12, 17-trimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer pair 1, enantiomer 2) (compound 216) (9.1mg, 58%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.39(s, 1H), 7.57(d, J ═ 8.5Hz, 1H), 7.38(s, 1H), 7.10-6.82(m, 2H), 6.68(d, J ═ 30.7Hz, 1H), 4.17(s, 1H), 4.03-3.79(m, 2H), 3.46(p, J ═ 8.5, 7.9Hz, 2H), 3.21(dd, J ═ 10.3, 6.1Hz, 2H), 3.00(s, 2H), 2.10(s, 1H), 1.79(d, J ═ 10.2Hz, 1H), 1.52(d, J ═ 50.3Hz, 9H), 1.40(t, J ═ 8.1Hz, 2H), 1.28 (d, J ═ 40, 3.92, 3.03H, 3H), 1.40 (d, 3.6.1 Hz, 3H). ESI-MS M/z calculated 597.30975, Experimental 598.2(M +1)⁺(ii) a Retention time: 2.06min (LC method B).

And 7: 8- [3- (3, 3-dimethylbutyl) -2-oxoimidazolidin-1-yl radical]-12, 12, 17-trimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer pair 2, enantiomer 1) (compound 218) and 8- [3- (3, 3-dimethylbutyl) -2-oxoimidazolidin-1-yl]-12, 12, 17-trimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer pair 2, enantiomer 2) (compound 219)

P-8- [3- (3, 3-dimethylbutyl) -2-oxoimidazolidin-1-yl]-12, 12, 17-trimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Chiral SFC chromatography of tetracosene-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer pair 2) (compound 210) (60mg) was performed using the following SFC scheme: phenomenex LUX-4 AS-H (250X 10mm), 5 μm; mobile phase: 42% methanol (no modifier), 58% carbon dioxide; 70 μ L was injected at 24mg/mL in methanol at 10 mL/min. The first enantiomer to be eluted is 8- [3- (3, 3-dimethylbutyl) -2-oxoimidazolidin-1-yl]-12, 12, 17-trimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosane-1 (22), 5, 79, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer pair 2, enantiomer 1) (compound 218) (9mg, 30%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.11(s, 1H), 7.56(t, J ═ 7.8 Hz, 1H), 7.51-7.31(m, 2H), 7.15(d, J ═ 7.3Hz, 2H), 6.68(d, J ═ 8.5Hz, 1H), 4.03-3.80 (m, 1H), 3.45(t, J ═ 8.3Hz, 2H), 3.25-3.16(m, 2H), 3.08(s, 2H), 2.25(d, J ═ 21.1Hz, 1H), 1.84(dd, J ═ 11.9, 5.8Hz, 1H), 1.71(s, 1H), 1.57(s, 3H), 1.49(s, 4H), 1.47-1.33(m, 3H), 1.29-1.17(m, 7H), 0.9 (s, 9H). ESI-MS M/z calculated 597.30975, Experimental 598.36(M +1)⁺(ii) a Retention time: 0.82min (LC method A). The second enantiomer to be eluted is 8- [3- (3, 3-dimethylbutyl) -2-oxoimidazolidin-1-yl]-12, 12, 17-trimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer vs. 2, enantiomer 2) (compound 219) (14mg, 46%). ESI-MS M/z calculated 597.30975, experimental 598.33(M +1)⁺(ii) a Retention time: 2.11min (LC method B).

Example 59: preparation of (14S) -8- {3- [ (4, 4-dimethylcyclohexyl) methyl]-2-oxoimidazolidin-1-yl } -12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 217)

Step 1: n- [2- [ (4, 4-dimethylcyclohexyl) methylamino ] ethyl ] carbamic acid tert-butyl ester

To a stirred solution of 4, 4-dimethylcyclohexanecarboxaldehyde (250mg, 1.783mmol) in dry methanol (10mL) under nitrogen was added N- (2-amino)Ethyl) carbamic acid tert-butyl ester (286mg, 1.785mmol) and dry methanol (1 mL). After stirring the yellow solution at ambient temperature for 1h, it was cooled to 0 ℃ (ice-water bath) then sodium borohydride (142mg, 3.753mmol) was added slowly in two portions and the mixture was allowed to warm to ambient temperature and stirring was continued for 15 h. The volatiles were removed under reduced pressure the residue was dissolved in ethyl acetate (30mL) and washed with saturated aqueous sodium bicarbonate (2 × 15mL) and brine (15mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give N- [2- [ (4, 4-dimethylcyclohexyl) methylamino) as a yellow gum]Ethyl radical]Tert-butyl carbamate (481mg, 95%). the crude material was used in the next step without further purification ESI-MS M/z calculated 284.24637, experimental 285.3(M +1) ⁺(ii) a Retention time: 1.04min (LC method B).

Step 2: 1- [ (4, 4-dimethylcyclohexyl) methyl ] imidazolidin-2-one

Solid potassium tert-butoxide (300mg, 2.674mmol) was added to N- [2- [ (4, 4-dimethylcyclohexyl) methylamino under nitrogen]Ethyl radical]Tert-butyl carbamate (240mg, 0.8438mmol) in anhydrous tetrahydrofuran (12 mL) and the reaction mixture was heated at 70 ℃ for 13 h. The heterogeneous mixture was cooled to ambient temperature and acidified with hydrochloric acid (3.5mL, 1.0M, 3.500 mmol). Volatiles were removed under reduced pressure (not dry). The aqueous residue was extracted with ethyl acetate (3 × 10mL) and the organic layers were combined, washed with brine (10mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure the residue was purified by silica gel chromatography (gradient of 0% to 10% methanol/dichloromethane over 30min) to give 1- [ (4, 4-dimethylcyclohexyl) methyl ] hydride as an off-white solid]Imidazolidin-2-one (62mg, 35%).¹H NMR (400MHz, benzene-d)₆)5.42(s, 1H), 3.10(d, J ═ 7.3Hz, 2H), 2.84-2.77(m, 2H), 2.77-2.71(m, 2H), 1.58-1.52(m, 2H), 1.46-1.42 (m, 2H), 1.38(dq, J ═ 10.7, 3.5Hz, 1H), 1.27-1.20(m, 2H), 1.19-1.12(m, 2H), 1.00(s, 3H), 0.92(s, 3H) ESI-MS m/z Value 210.17322, Experimental value 211.2(M +1)⁺(ii) a Retention time: 1.17min (LC method B).

And step 3: (14S) -8- {3- [ (4, 4-Dimethylcyclohexyl) methyl group]-2-oxoimidazolidin-1-yl } -12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 217)

4mL vials were sequentially charged with (14S) -8-chloro-12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (50mg, 0.1111mmol), 1- [ (4, 4-dimethylcyclohexyl) methyl]Imidazolidin-2-one (26mg, 0.1236mmol), cesium carbonate (130mg, 0.3990mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (10mg, 0.01728 mmol) (Xantphos), and anhydrous dioxane (1.5 mL). Nitrogen was purged through the heterogeneous mixture for 2 min. Subsequently, tris (dibenzylideneacetone) dipalladium (0) (10mg, 0.01092mmol) was added under nitrogen and nitrogen was again purged through the mixture for 2min and the vial was capped under nitrogen. The mixture was stirred at 115 ℃ overnight the mixture was cooled to ambient temperature and neutralized with glacial acetic acid (60 μ L, 1.055 mmol). The volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.5mL) and filtered through a Whatman 0.45 μm PTFE syringe filter using preparative reverse phase HPLC-MS (Luna C sold by Phenomenex) ₁₈(2) The sample was purified on a column (75X 30mm, 5 μm particle size) (pn: 00C-4252-U0-AX) by 15min double gradient run of 30-99% acetonitrile/water (hydrochloric acid as modifier). The desired product fractions were combined and concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (25 mL) and washed with brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (14S) -8- {3- [ (4, 4-dimethylcyclohexyl) methyl group as a pale yellow solid]-2-oxoimidazolidin-1-yl } -12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 217) (7.5mg, 11%).¹H NMR (400 MHz, methanol-d)₄)7.70(d, J ═ 8.6Hz, 1H), 7.52(dd, J ═ 8.5, 7.2Hz, 1H), 7.43(d, J ═ 8.6Hz, 1H), 7.15(dd, J ═ 7.2, 0.8Hz, 1H), 6.65(dd, J ═ 8.5, 0.8Hz, 1H), 4.10-4.07 (m, 1H), 4.07-4.02(m, 1H), 4.02-3.95(m, 1H), 3.56-3.52(m, 1H), 3.51-3.47(m, 1H), 3.23(dd, J ═ 10.2, 6.7Hz, 1H), 3.18-3.09(m, 2H), 3.07-2.98(m, 2H), 2.86(t, 86, 1H), 3.3.3.55H), 3.3.3.3.3.3 (m, 1H), 3.3.3.3.3.3.3.3.3.3.3.35H), 3.3.3.3.3.3.3.3.3 (m, 1H), 3.3.3.3.3.3.3.3, 3, 3.6, 3.3.3, 3, 3.3, 3, 2H) 1.22-1.16 (m, 3H), 0.91(s, 6H). ESI-MS M/z calculated 623.3254, Experimental 624.4(M +1) ⁺(ii) a Retention time: 2.13min (LC method B).

Example 60: preparation of 12, 12-dimethyl-8- {3- [ 3-methyl-2- (prop-2-yl) butoxy]-1H-pyrazol-1-yl } -2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaene-2, 2, 4-trione (compound 220)

Step 1: 3- (2-isopropyl-3-methyl-butoxy) pyrazole-1-carboxylic acid tert-butyl ester

A solution of 2-isopropyl-3-methyl-butan-1-ol (500mg, 3.839mmol), tert-butyl 3-hydroxypyrazole-1-carboxylate (705mg, 3.828mmol) and triphenylphosphine (1.16g, 4.423mmol) in anhydrous tetrahydrofuran (20mL) was cooled in an ice bath and DIAD (830. mu.L, 4.216mmol) was added slowly under a nitrogen atmosphereThe residue was purified by silica gel chromatography using a gradient of 0-50% ethyl acetate/hexanes to give tert-butyl 3- (2-isopropyl-3-methyl-butoxy) pyrazole-1-carboxylate (980mg, 86%) as a clear oil.¹H NMR (400MHz, chloroform-d) 7.82(d, J ═ 3.0Hz, 1H), 5.84(d, J ═ 2.9Hz, 1H), 4.29(d, J ═ 4.8Hz, 2H), 1.91(pd, J ═ 6.9, 5.6Hz, 2H), 1.61(s, 9H), 1.44-1.24(M, 1H), 0.98(d, J ═ 6.8Hz, 6H), 0.92(d, J ═ 6.9Hz, 6H), ESI-MS M/z calculated 296.21, experimental 297.21(M +1) ⁺(ii) a Retention time: 0.84min (LC method A).

Step 2: 3- (2-isopropyl-3-methyl-butoxy) -1H-pyrazole

In a 250mL round bottom flask was placed 3- (2-isopropyl-3-methyl-butoxy) pyrazole-1-carboxylic acid tert-butyl ester (980mg, 3.306mmol), dichloromethane (10mL), and methanol (10 mL). To this clear solution was added hydrogen chloride-containing 1, 4-dioxane (4.1mL, 4M, 16.40mmol) by syringe. The homogeneous solution was stirred at 45 ℃ for 19h. 1, 4-dioxane containing two further equivalents of 4M hydrogen chloride was added and stirred for an additional hour the volatiles were removed under reduced pressure the residue was dissolved in ethyl acetate (50mL) and washed with 1N aqueous sodium hydroxide. The combined organic extracts were washed with brine, dried over sodium sulfate, and the solvent was evaporated to give 3- (2-isopropyl-3-methyl-butoxy) -1H-pyrazole as a colorless oil (490mg, 76%). ESI-MS M/z calculated 196.15756, Experimental 197.1 (M +1)⁺(ii) a Retention time: 0.72min (LC method A).

And step 3: 2-chloro-6- [3- (2-isopropyl-3-methyl-butoxy) pyrazol-1-yl ] pyridine-3-carboxylic acid ethyl ester

Ethyl 2, 6-dichloropyridine-3-carboxylate (547mg, 2.486mmol), 3- (2-isopropyl-3-methyl-butoxy) -1H-pyrazole (488mg, 2.486mmol) and potassium carbonate (412mg, 2.981mmol) were combined in anhydrous dimethylsulfoxide (6mL) and 1, 4-diazabicyclo [2.2.2 mmol ] was added ]Octane (56mg, 0.4992mmol) and the mixture stirred at room temperature under nitrogen for 16 h. The reaction mixture was diluted with water (80mL) and stirred for 15min]Pyridine-3-carboxylic acid ethyl ester (900mg, 95%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)8.42(d, J ═ 2.9Hz, 1H), 8.39(d, J ═ 8.5Hz, 1H), 7.76(d, J ═ 8.4Hz, 1H), 6.20(d, J ═ 2.9Hz, 1H), 4.34(q, J ═ 7.1Hz, 2H), 4.26(d, J ═ 4.8Hz, 2H), 2.02-1.76(m, 2H), 1.45-1.29 (m, 4H), 0.98(d, J ═ 6.8Hz, 6H), 0.92(d, J ═ 6.8Hz, 6H). ESI-MS M/z calculated 379.16626, Experimental 380.21(M +1)⁺(ii) a Retention time: 2.56min (LC method B).

And 4, step 4: 2-chloro-6- [3- (2-isopropyl-3-methyl-butoxy) pyrazol-1-yl ] pyridine-3-carboxylic acid

Adding 2-chloro-6- [3- (2-isopropyl-3-methyl-butoxy) pyrazol-1-yl to a round-bottom flask]Pyridine-3-carboxylic acid ethyl ester (900mg, 2.369mmol), tetrahydrofuran (6mL) and aqueous sodium hydroxide (1.4mL, 5M, 7.000mmol). the reaction solution was stirred at room temperature for 4 h. The reaction solution was diluted with ethyl acetate (100mL) and aqueous hydrochloric acid (12mL, 1M, 12.00mmol) was added the phases were separated and the aqueous solution was extracted with ethyl acetate (2 × 30 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give 2-chloro-6- [3- (2-isopropyl-3-methyl-butoxy) pyrazol-1-yl ]Pyridine-3-carboxylic acid (655mg, 79%) used without further purification ESI-MS M/z calculated 351.13498, Experimental 352.19(M +1)⁺(ii) a Retention time: 0.87min (LC method A).

And 5: 5- [3- [ [6- [ [ 2-chloro-6- [3- (2-isopropyl-3-methyl-butoxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- (2-isopropyl-3-methyl-butoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (170mg, 0.4832 mmol) and carbonyldiimidazole (81mg, 0.4995mmol) were combined in dry tetrahydrofuran (4mL) and stirred at 40 ℃ for 75min, followed by addition of 2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (165mg, 0.400mmol) and 1, 8-diazabicyclo [5.4.0]A solution of undec-7-ene (152. mu.L, 1.016mmol) in tetrahydrofuran (7mL) the reaction was heated at 50 ℃ for 4 h. The organic layer was dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexane to 75% ethyl acetate/hexane to give 5- [3- [ [6- [ [ 2-chloro-6- [3- (2-isopropyl-3-methyl-butoxy) pyrazol-1-yl ] as an off-white solid ]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (200mg, 67%). ESI-MS calculated M/z 745.3388, Experimental 746.3(M +1)⁺(ii) a Retention time: 0.87min (LC method K).

Step 6: 12, 12-dimethyl-8- {3- [ 3-methyl-2- (prop-2-yl) butoxy]-1H-pyrazol-1-yl } -2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaene-2, 2, 4-trione (compound 220)

Reacting 5- [3- [ [6- [ [ 2-chloro-6- [3- (2-isopropyl-3-methyl-butoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (200mg, 0.2680 mmol) was dissolved in dichloromethane (3.5mL) and hydrochloric acid (4mL, 4M in dioxane, 16.00mmol) was added to the mixture. The mixture was stirred at room temperature for 2h. This residue was mixed with potassium carbonate (223mg, 1.614mmol), cesium fluoride (66mg, 0.4345 mmol),

Molecular sieves and dimethylsulfoxide (3.2mL) were combined in a vial, purged with nitrogen, capped, heated to 140 ℃ and stirred for 16 h. The reaction mixture was cooled to room temperature, filtered, and then subjected to reverse-phase preparative chromatography (C) ₁₈Column, 30% to 99% acetonitrile (no modifier)/water (5mM hydrochloric acid) gradient purified over 30min to give 12, 12-dimethyl-8- {3- [ 3-methyl-2- (propan-2-yl) butoxy as a white solid]-1H-pyrazol-1-yl } -2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 220) (65mg, 39%). ESI-MS M/z Calculation 609.30975, Experimental value 610.47(M +1)⁺(ii) a Retention time: 2.52min (LC method B).

Example 61: preparation of (18S) -20, 20-dimethyl-4- [3- (4, 4, 4-trifluoro-3, 3-dimethylbutoxy) -1H-pyrazol-1-yl]-10λ⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (compound 221)

Step 1: (4S) -4- [3- [3- [ [ 2-chloro-6- [3- (4, 4, 4-trifluoro-3, 3-dimethyl-butoxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] pyrazol-1-yl ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- (4, 4, 4-trifluoro-3, 3-dimethyl-butoxy) -pyrazol-1-yl at room temperature]A solution of pyridine-3-carboxylic acid tert-butyl ester (150mg, 0.3457mmol) in trifluoroacetic acid (150 μ L, 1.947mmol) in dichloromethane (400 μ L) was stirred for 2h removing the solvent and the residue dried in vacuo this material was dissolved in tetrahydrofuran (2mL) and carbonyldiimidazole (69mg, 0.4255mmol) was added and the reaction mixture was stirred at room temperature for 4h, then (4S) -2, 2-dimethyl-4- [3- (3-sulfamoylpyrazol-1-yl) propyl containing ]Pyrrolidine-1-carboxylic acid tert-butyl ester (136mg, 0.3519mmol) in tetrahydrofuran (2mL) followed by the addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (110 μ L, 0.7356mmol) and the reaction stirred for 16h the reaction was diluted with ethyl acetate and washed with a saturated ammonium chloride/brine mixture (1: 1) the organic layer was separated, dried over sodium sulfate, filtered and evaporated. The resulting brown residue was purified by silica gel chromatography using a gentle gradient from 100% dichloromethane to 20% methanol/dichloromethane to give (4S) -4- [3- [3- [ [ 2-chloro-6- [3- (4, 4, 4-trifluoro-3, 3-dimethyl-butoxy) pyrazol-1-yl as a white solid]Pyridine-3-carbonyl]Sulfamoyl radical]Pyrazol-1-yl]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (82mg, 32%). ESI-MS M/z calculated 745.2636, Experimental 746.14(M +1)⁺(ii) a Retention time: 0.87min (LC method A).

Step 2: (18S) -20, 20-dimethyl-4- [3- (4, 4, 4-trifluoro-3, 3-dimethylbutoxy) -1H-pyrazol-1-yl]-10λ⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (compound 221)

(4S) -4- [3- [3- [ [ 2-chloro-6- [3- (4, 4, 4-trifluoro-3, 3-dimethyl-butoxy) pyrazol-1-yl at room temperature ]Pyridine-3-carbonyl]Sulfamoyl radical]Pyrazol-1-yl]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (82mg, 0.1099mmol) in dichloromethane (400. mu.L) and trifluoroacetic acid (100. mu.L, 1.307 mm)ol) was stirred for 2h after the reaction was complete, the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with a saturated solution of sodium bicarbonate (2mL), and the organic layer was collected and the solvent was evaporated the resulting residue was dissolved in dimethyl sulfoxide (5mL) and added

Molecular sieving and stirring the reaction mixture for 10min then cesium fluoride (54 mg, 0.3555mmol) and potassium carbonate (48mg, 0.3473mmol) were added and the reaction mixture was heated at 130 ℃ overnight the reaction mixture was filtered through Whatman filter disc (puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS method using a double gradient run of 50-99% mobile phase B over 15.0min (mobile phase a ═ water (0.05% hydrochloric acid), mobile phase B ═ acetonitrile) to give (18S) -20, 20-dimethyl-4- [3- (4, 4, 4-trifluoro-3, 3-dimethylbutoxy) -1H-pyrazol-1-yl as a white solid]-10λ⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (compound 221) (14.3mg, 21%). ¹H NMR (400MHz, chloroform-d) 8.40(s, 1H), 8.18(d, J ═ 2.8Hz, 1H), 7.68(d, J ═ 8.2Hz, 1H), 7.48(d, J ═ 2.3Hz, 1H), 7.07(d, J ═ 2.3Hz, 1H), 7.02 (d, J ═ 8.3Hz, 1H), 5.87(d, J ═ 2.7Hz, 1H), 4.36(q, J ═ 7.0Hz, 3H), 3.94(t, J ═ 12.0 Hz, 1H), 2.74(t, J ═ 8.2Hz, 1H), 2.14(s, 2H), 2.02(t, J ═ 7.2Hz, 3H), 1.76(dd, J ═ 11.8, 8.2Hz, 1H), 5.5 (d, J ═ 2H, 1H), 5.3.3.3.3.3H, 5 (t, 5H, 5M ═ 2H, 5 (M, 1H, 5M, 5, 1H), calculated values (M, 1H, 3, 1H, 3, 1H.⁺(ii) a Retention time: 2.17min (LC method B).

Example 62: preparation of (14S) -12, 12-dimethyl-8- [ 2-oxo-3- (4, 4, 4-trifluoro-3, 3-dimethylbutyl) imidazolidin-1-yl]-2λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 223)

Step 1: n- [2- [ (4, 4, 4-trifluoro-3, 3-dimethyl-butyl) amino ] ethyl ] carbamic acid tert-butyl ester

Dess-martin periodinane (660mg, 1.556mmol) was added to a stirred solution of 4, 4, 4-trifluoro-3, 3-dimethyl-butan-1-ol (210mg, 1.345mmol) in anhydrous dichloromethane (7mL) at 0 ℃ (ice water bath) under nitrogen after 15min the bath was removed and the reaction was allowed to warm to ambient temperature and stirring continued for an additional 2 h. The reaction was diluted with ether (60mL) and a saturated aqueous solution of sodium bicarbonate (20mL) was added slowly (carbon dioxide gas evolution was observed), followed by addition of sodium thiosulfate (10mL) and stirring at ambient temperature for 30min. The combined organics were washed with brine (20mL), dried over anhydrous sodium sulfate, filtered and partially concentrated under reduced pressure (to about 2mL volume) to obtain the intermediate aldehyde as a crude solution. Next, to a stirred solution of tert-butyl N- (2-aminoethyl) carbamate (216mg, 1.348 mmol) in dry methanol (7mL) under nitrogen was added the ethereal solution of the previously obtained intermediate aldehyde in dry methanol (1 mL) after stirring the yellow solution at ambient temperature for 1h, it was cooled to 0 deg.C (ice water bath). subsequently, sodium borohydride (110mg, 2.908mmol) was slowly added in two portions and the mixture was allowed to warm to ambient temperature and stirring was continued for 15h. The residue was dissolved in ethyl acetate (30mL) and washed with saturated aqueous sodium bicarbonate (2 × 15mL) and brine (15mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give N- [2- [ (4, 4, 4-trifluoro-3, 3-dimethyl-butyl) amino as a clear viscous oil ]Ethyl radical]Tert-butyl carbamate (380mg, 95%). ESI-MS M/z calculated 298.1868, Experimental value 299.2(M +1)⁺(ii) a Retention time: 0.82min (LC method B).

Step 2: 1- (4, 4, 4-trifluoro-3, 3-dimethyl-butyl) imidazolidin-2-one

Solid potassium tert-butoxide (440mg, 3.921mmol) was added to N- [2- [ (4, 4, 4-trifluoro-3, 3-dimethyl-butyl) amino under nitrogen]Ethyl radical]Tert-butyl carbamate (380mg, 1.274mmol) in a stirred solution in anhydrous tetrahydrofuran (12mL) and the reaction mixture was heated at 70 ℃ for 13h. The aqueous residue was extracted with ethyl acetate (3 × 10mL) and the combined organics were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient of 0% to 10% methanol in dichloromethane over 30min) to give 1- (4, 4, 4-trifluoro-3, 3-dimethyl-butyl) imidazolidin-2-one as an off-white solid (172mg, 60%).¹H NMR (400MHz, benzene-d)₆)5.50(s, 1H), 3.23-3.12(m, 2H), 2.71-2.66(m, 2H), 2.65-2.59(m, 2H), 1.64-1.53(m, 2H), 1.01(s, 6H).19F NMR (376MHz, methanol-d 4) 79.87. ESI-MS M/z calculated 224.11365, Experimental value 225.1(M +1) ⁺(ii) a Retention time: 1.08min (LC method B).

And step 3: (14S) -12, 12-dimethyl-8- [ 2-oxo-3- (4, 4, 4-trifluoro-3, 3-dimethylbutyl) imidazolidin-1-yl]-2λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 223)

Sequentially add (14S) -8-chloro-12, 12-dimethyl-2. lambda. to a 4mL vial⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (51mg, 0.1133mmol), 1- (4, 4, 4-trifluoro-3, 3-dimethyl-butyl) imidazolidin-2-one (31mg, 0).1383mmol), cesium carbonate (130mg, 0.3990mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (10mg, 0.01728mmol), and anhydrous dioxane (1.5mL). Subsequently, tris (benzylidene acetone) dipalladium (0) (10mg, 0.01092mmol) was added under nitrogen and nitrogen was bubbled for an additional 2min and the reaction capped under nitrogen. The mixture was stirred at 115 ℃ overnight. The mixture was cooled to ambient temperature and neutralized with glacial acetic acid (50 μ L, 0.8792 mmol.) the volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.2mL) and filtered through a Whatman 0.45 μm PTFE syringe filter. Using preparative reverse phase HPLC [ Luna C sold by Phenomenex ₁₈(2) Column (75X 30mm, 5 μm particle size) (pn: 00C-4252-U0-AX), (double gradient run over 15min of 30-99% acetonitrile/water (hydrochloric acid as modifier)]The desired product fractions were combined and concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (25mL) and washed with brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain (14S) -12, 12-dimethyl-8- [ 2-oxo-3- (4, 4, 4-trifluoro-3, 3-dimethylbutyl) imidazolidin-1-yl as a yellowish solid]-2λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 223) (37mg, 51%).¹H NMR (400MHz, methanol-d)₄)7.70(d, J ═ 8.6Hz, 1H), 7.52(dd, J ═ 8.5, 7.2Hz, 1H), 7.44(d, J ═ 8.6Hz, 1H), 7.15(dd, J ═ 7.2, 0.8Hz, 1H), 6.65(dd, J ═ 8.5, 0.8Hz, 1H), 4.10-4.07(m, 1H), 4.07-4.01(m, 1H), 4.01-3.95(m, 1H), 3.58-3.46 (m, 2H), 3.42-3.34(m, 2H), 3.23(t, J ═ 8.6Hz, 1H), 3.08-2.97(m, 1H), 2.85(t, J ═ 10.4, 1H), 2.23 (t, J ═ 8.6Hz, 1H), 3.08-2.97(m, 1H), 2.85(t, J ═ 10.4, 1H), 2.19 (m, 1H), 1.19 (m, 1H), 1H, 31, 1H, 18, 1H, 3.47 (m, 1H), 3.19, 1H), 5, experimental value 638.5(M +1) ⁺(ii) a Retention time: 1.9min (LC method B).

Example 63: preparation of (14S) -8- [ 3-fluoro-5- (2-methylpropoxy) phenyl]-12, 12-dimethyl-2 lambda⁶-sulfurHetero-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 224)

Step 1: 2-chloro-6- (3-fluoro-5-isobutoxy-phenyl) pyridine-3-carboxylic acid tert-butyl ester

Tert-butyl 2, 6-dichloropyridine-3-carboxylate (15.0g, 60.5mmol) and (3-fluoro-5-isobutoxy-phenyl) boronic acid (13.46g, 63.48mmol) were combined and dissolved well in ethanol (150mL) and toluene (150 mL). A suspension of sodium carbonate (19.23g, 181.4mmol) in water (30mL) was added. Tetrakis (triphenylphosphine) palladium (0) (2.096g, 1.814mmol) was added under nitrogen the reaction mixture was stirred at 60 ℃ for 16h, volatiles were removed under reduced pressure, the remaining solid was partitioned between water (100mL) and ethyl acetate (100mL), the organic layer was washed with brine (1 × 100mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The material was subjected to silica gel column chromatography (gradient 0% to 20% ethyl acetate/hexane). This material was repurified by silica gel chromatography (isocratic 100% hexane for 10min, followed by a 0 to 5% ethyl acetate/hexane gradient) to give tert-butyl 2-chloro-6- (3-fluoro-5-isobutoxy-phenyl) pyridine-3-carboxylate (18.87g, 49.68mmol, 82%) as a colorless oil obtained. ¹H NMR (400MHz, dimethylsulfoxide-d)₆)8.24(d, J ═ 8.0Hz, 1H), 8.16(d, J ═ 8.1Hz, 1H), 7.48(dd, J ═ 9.4, 2.0Hz, 2H), 6.99(dt, J ═ 10.8, 2.2Hz, 1H), 3.86(d, J ═ 6.5Hz, 2H), 2.05(dt, J ═ 13.3, 6.6Hz, 1H), 1.57(d, J ═ 9.3Hz, 9H), calculated value 1.00(t, J ═ 5.5Hz, 6H), ESI-MS M/z 379.13504, experimental value 380.2(M +1)⁺(ii) a Retention time: 2.57min (LC method B).

Step 2: 2-chloro-6- (3-fluoro-5-isobutoxy-phenyl) pyridine-3-carboxylic acid

Tert-butyl 2-chloro-6- (3-fluoro-5-isobutoxy-phenyl) pyridine-3-carboxylate (18.57g, 48.89mmol) was dissolved in dichloromethane (200 mL.) trifluoroacetic acid (60mL, 780mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was stirred at 40 ℃ for 2h. The solution was washed with a saturated aqueous solution of sodium bicarbonate (1 × 100mL) and brine (1 × 100mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was suspended in ethyl acetate (75mL) and washed with aqueous hydrochloric acid (1N, 1X 75 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid (17.7g) was stirred at 40 ℃ for 30min as a slurry in dichloromethane (35mL) after cooling to room temperature, the slurry was filtered and then rinsed with low temperature dichloromethane to give 2-chloro-6- (3-fluoro-5-isobutoxy-phenyl) pyridine-3-carboxylic acid as a white solid (11.35g, 35.06mmol, 72%). ¹H NMR (400MHz, dimethylsulfoxide-d)₆)13.76(s, 1H), 8.31(d, J ═ 8.0Hz, 1H), 8.17(d, J ═ 8.1Hz, 1H), 7.54-7.47(m, 2H), 7.00(dt, J ═ 10.8, 2.3Hz, 1H), 3.87(d, J ═ 6.5 Hz, 2H), 2.05(dt, J ═ 13.3, 6.6Hz, 1H), 1.01(d, J ═ 6.7Hz, 6H). ESI-MS M/z calculated 323.1, Experimental 324.1(M +1)⁺(ii) a Retention time: 1.96min (LC method B).

And step 3: (4S) -4- [3- [ [6- [ [ 2-chloro-6- (3-fluoro-5-isobutoxy-phenyl) pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

In a 20mL scintillation vial, 2-chloro-6- (3-fluoro-5-isobutoxy-phenyl) pyridine-3-carboxylic acid (156mg, 0.3751mmol) and carbonyldiimidazole (61mg, 0.3762mmol) were combined in tetrahydrofuran (2mL) and stirred at room temperature for 2 h. Subsequently, (4S) -2, 2-dimethyl-4- [3- [ (6-sulfamate) was addedAcyl-2-pyridyl) amino]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (100mg, 0.2424mmol) in tetrahydrofuran (2mL) followed by the addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (110 μ L, 0.7356mmol) and the reaction stirred for 16 h. The reaction was diluted with ethyl acetate and washed with a small amount of 1: 1 saturated aqueous ammonium chloride solution/brine the organics were separated, dried over sodium sulfate, filtered and evaporated. The resulting brown residue was purified by silica gel chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate to give (4S) -4- [3- [ [6- [ [ 2-chloro-6- (3-fluoro-5-isobutoxy-phenyl) pyridine-3-carbonyl ]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (116mg, 67%). ESI-MS M/z calculated 717.2763, Experimental 718.38(M +1)⁺(ii) a Retention time: 0.95min (LC method A).

And 4, step 4: (14S) -8- [ 3-fluoro-5- (2-methylpropoxy) phenyl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 224)

(4S) -4- [3- [ [6- [ [ 2-chloro-6- (3-fluoro-5-isobutoxy-phenyl) pyridine-3-carbonyl ] at room temperature]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]A solution of tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (110mg, 0.1531mmol) in dichloromethane (1mL) and trifluoroacetic acid (200 μ L, 2.614mmol) was stirred for 4h then the solvent was evaporated the residue was dissolved in ethyl acetate, washed with 2mL saturated solution of sodium bicarbonate and the solvent was evaporated and dried in vacuo. The resulting residue was dissolved in dimethyl sulfoxide (5mL) and added

Molecular sieves and stirring the reaction mixture for 10min then cesium fluoride (76mg, 0.5003mmol) and potassium carbonate (64 mg, 0.4631mmol) were added and the reaction mixture was heated at 150 ℃ for 16h, filtered through a Whatman filter disc (puradisc 25 TF) and And the filtrate was purified by reverse phase HPLC-MS method using a double gradient run of 20-80% mobile phase B (mobile phase a ═ water (0.05% hydrochloric acid), mobile phase B ═ acetonitrile) over 15.0min to give (14S) -8- [ 3-fluoro-5- (2-methylpropoxy) phenyl ] phenyl as an off-white solid]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 224) (12.5mg, 14%).¹H NMR (400MHz, chloroform-d) 10.39(s, 1H), 8.08(d, J ═ 8.1Hz, 1H), 7.60-7.46(m, 2H), 7.36(t, J ═ 1.9Hz, 1H), 7.33-7.21 (m, 2H), 6.68(dt, J ═ 10.4, 2.3Hz, 1H), 6.57(dd, J ═ 7.8, 1.4Hz, 1H), 4.75(s, 1H), 3.90(s, 1H), 3.77(d, J ═ 6.6Hz, 2H), 3.36(t, J ═ 8.7Hz, 1H), 3.17(d, J ═ 12.6Hz, 1H), 3.08(t, J ═ 9.6, 1H), 2H (J ═ 69, J ═ 8.7Hz, 1H), 3.17(d, J ═ 12.6Hz, 1H), 3.08(t, J ═ 9.6, 1H, 69, J ═ 6, 1H), 3.65 (J ═ 7H, 1H), 1H, 13 (z, 1H), 13, 1H, 13, m ═ 6H, 1H, 13, 5 (z, 5, m ═ 6, 1H, experimental value 582.34(M +1)⁺(ii) a Retention time: 1.24min (LC method J).

Example 64: preparation of (18S) -4- [ 3-fluoro-5- (2-methylpropoxy) phenyl ]-20, 20-dimethyl-10. lambda.⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione

Step 1: (4S) -4- [3- [3- [ [ 2-chloro-6- (3-fluoro-5-isobutoxy-phenyl) pyridine-3-carbonyl ] sulfamoyl ] pyrazol-1-yl ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

In a 20mL scintillation vial, 2-chloro-6- (3-fluoro-5-isobutoxy-phenyl) pyridine-3-carboxylic acid (71mg, 0.1707mmol) and carbonyldiimidazole (27mg, 0.1665mmol) were combined in tetrahydrofuranPyran (2mL) and stirred at room temperature for 6h. Subsequently, (4S) -2, 2-dimethyl-4- [3- (3-sulfamoylpyrazol-1-yl) propyl group-containing compound was added]Pyrrolidine-1-carboxylic acid tert-butyl ester (50mg, 0.1294mmol) in tetrahydrofuran (2mL) followed by the addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (42 μ L, 0.2809mmol) and the reaction stirred at room temperature for 16h the reaction was diluted with ethyl acetate and washed with a small amount of 1: 1 saturated aqueous ammonium chloride solution/brine the organics were separated, dried over sodium sulfate, filtered and evaporated. The resulting brown residue was purified by silica gel chromatography using a gentle gradient from 100% dichloromethane to 20% methanol/dichloromethane to give (4S) -4- [3- [3- [ [ 2-chloro-6- (3-fluoro-5-isobutoxy-phenyl) pyridine-3-carbonyl as a white solid ]Sulfamoyl radical]Pyrazol-1-yl]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (52mg, 58%). ESI-MS calculated M/z 691.2607, Experimental 692.0 (M +1)⁺(ii) a Retention time: 0.92min (LC method A).

Step 2: (18S) -4- [ 3-fluoro-5- (2-methylpropoxy) phenyl]-20, 20-dimethyl-10. lambda.⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione

(4S) -4- [3- [3- [ [ 2-chloro-6- (3-fluoro-5-isobutoxy-phenyl) pyridine-3-carbonyl ] at room temperature]Sulfamoyl radical]Pyrazol-1-yl]Propyl radical]A solution of tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (52mg, 0.07512mmol) in dichloromethane (500. mu.L) and trifluoroacetic acid (100. mu.L, 1.307mmol) was stirred for 4 h. The solvent is subsequently evaporated. The residue was dissolved in ethyl acetate, washed with 2mL of saturated solution of sodium bicarbonate, and the solvent was removed and dried under high vacuum to give a residue dissolved in dimethyl sulfoxide (5mL), and added

Molecular sieves and stir the reaction mixture for 10 min. Subsequently, cesium fluoride (38mg, 0.2502mmol) and potassium carbonate (34 mg, 0.2460mmol) were added, andthe reaction mixture was heated at 150 ℃ for 16h. the reaction mixture was filtered through Whatman filter disc (puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS method using a double gradient run of 50-99% mobile phase B over 15.0min (mobile phase a ═ water (0.05% hydrochloric acid), mobile phase B ═ acetonitrile) to give (18S) -4- [ 3-fluoro-5- (2-methylpropoxy) phenyl as an off-white solid ]-20, 20-dimethyl-10. lambda.⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [ [16.2.1.111, 14.02, 7 ]]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (14.0mg, 34%).¹H NMR (400MHz, chloroform-d) 7.65(d, J ═ 7.9Hz, 1H), 7.47(d, J ═ 2.3Hz, 1H), 7.35-7.32(m, 1H), 7.28-7.23(m, 1H), 7.08(s, 1H), 6.95(d, J ═ 7.9Hz, 1H), 6.64(dt, J ═ 10.4, 2.3Hz, 1H), 4.33(d, J ═ 13.3Hz, 1H), 3.92(dd, J ═ 13.9, 11.2Hz, 1H), 3.75(d, J ═ 6.6Hz, 2H), 2.75(s, 1H), 2.21-2.07(m, 3H), 1.98(dd, J ═ 3.19, 10.6Hz, 1H), 1.75 (s, 1H), 2.21-2.07(m, 3H), 1.98(dd, J ═ 3.3H), 1.19, 10.6H), 1.70H, 1H), 3.3.3.3.3.3H, 3.3.3H, 3.3.3.3.3H, 1H, 3.3.3.3H, 3H, 3.3H, 3H, 2H) in that respect ESI-MS M/z calculated 555.23157, Experimental 556.14(M +1)⁺(ii) a Retention time: 1.09 min (LC method J).

Example 65: preparation of (14S) -12, 12-dimethyl-8- {3- [ 3-methyl-2- (prop-2-yl) butoxy]-1H-pyrazol-1-yl } -2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 227)

Step 1: (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (2-isopropyl-3-methyl-butoxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

The reaction mixture was charged with carbonyldiimidazole (76mg, 0.4687mmol) and 2-chloro-6- [3- (2-isopropyl-3-methyl-butoxy) pyrazol-1-yl]A50 mL flask of pyridine-3-carboxylic acid (164mg, 0.4661mmol) was evacuated/backfilled with nitrogen (3X). Tetrahydrofuran (5mL) was added and the mixture was stirred at 50 ℃ for 1h, followed by addition of (4S) -2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (160mg, 0.3878mmol) and 1, 8-diazabicyclo [5.4.0]A solution of undec-7-ene (150mg, 0.9853mmol) in tetrahydrofuran (5mL) and the mixture stirred at 50 ℃ overnight the reaction was diluted with ethyl acetate and washed with water the organic phase was dried over sodium sulfate, evaporated in vacuo and purified by reverse phase HPLC ((C)₁₈): 1-99% acetonitrile/hydrochloric acid modifier (15min)) in water to give (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (2-isopropyl-3-methyl-butoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (90mg, 31%). ESI-MS M/z calculated 745.3388, Experimental 746.47(M +1) ⁺(ii) a Retention time: 1.96min (LC method B).

Step 2: 2-chloro-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] propylamino ] -2-pyridinyl ] sulfonyl ] -6- [3- (2-isopropyl-3-methyl-butoxy) pyrazol-1-yl ] pyridine-3-carboxamide (hydrochloride)

Reacting (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (2-isopropyl-3-methyl-butoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]A solution of tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (90mg, 0.12 mmol) in dioxane (5mL) was treated with 6M dioxane solution of hydrochloric acid (1.3mL, 7.800mmol) and stirred at room temperature for 3 h. The mixture was evaporated in vacuo to give 2-chloro-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] amine]Propylamino group]-2-pyridyl]Sulfonyl radical]-6- [3- (2-isopropyl-3-methyl-butoxy) pyrazol-1-yl]Pyridine-3-carboxamide (hydrochloride) (100mg, 38%). ESI-MS M/z calculated 645.2864, Experimental 646.36(M +1)⁺(ii) a Health-care productRetention time: 0.27min (LC method A).

And step 3: (14S) -12, 12-dimethyl-8- {3- [ 3-methyl-2- (prop-2-yl) butoxy]-1H-pyrazol-1-yl } -2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 227)

In a 5mL vial, potassium carbonate (102mg, 0.7380mmol), cesium fluoride (45mg, 0.2962 mmol) and

molecular sieves (300mg) and purged with nitrogen 2-chloro-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] was added]Propylamino group]-2-pyridyl]Sulfonyl radical]-6- [3- (2-isopropyl-3-methyl-butoxy) pyrazol-1-yl]A solution of pyridine-3-carboxamide (hydrochloride) (100mg, 0.1465mmol) in dimethyl sulfoxide (2mL) and the mixture stirred at 150 deg.C overnight the mixture was filtered and purified by preparative reverse phase HPLC ((C)₁₈): 50-99% acetonitrile/hydrochloric acid modifier in water (15min)) to give (14S) -12, 12-dimethyl-8- {3- [ 3-methyl-2- (propan-2-yl) butoxy-]-1H-pyrazol-1-yl } -2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 227) (18.0mg, 20%).¹H NMR (400MHz, chloroform-d) 9.99(s, 1H), 8.19(d, J ═ 2.8Hz, 1H), 8.07(d, J ═ 8.4Hz, 1H), 7.60-7.48(m, 2H), 7.30(d, J ═ 8.4Hz, 1H), 6.61-6.52(m, 1H), 5.91(d, J ═ 2.8Hz, 1H), 4.6-4.9(br.s, 1H), 4.28(d, J ═ 4.9Hz, 2H), 3.89(s, 1H), 3.35(dd, J ═ 9.9, 7.6Hz, 1H), 3.17(dd, J ═ 10.7, 6.7Hz, 1H), 3.06(t, J ═ 9.9, 2H, 7.6Hz, 1H), 1H, 9.9, 1H, 9, 1H, 2H, 9.9, 2H, 1H, 2H, 1H, 2H, 9, 1H, 2H, 1H, 9, 1H, 9H, 1H, 9H, 6H) ESI-MS calculated m/z 609.30975, experimental values 610.39(M+1)⁺(ii) a Retention time: 1.59min (LC method J).

Example 66: preparation of (14S) -8- {3- [2- (adamantan-1-yl) ethyl]-2-oxoimidazolidin-1-yl } -12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 228)

Step 1: 2- (1-adamantyl) acetaldehyde

After 15min, the bath was removed and the reaction was allowed to warm to ambient temperature and stirring continued for an additional 2h at 0 ℃ (ice water bath) solid dess-martin periodinane (825mg, 1.945mmol) was added to a stirred solution of 2- (1-adamantyl) ethanol (300mg, 1.664mmol) in anhydrous dichloromethane (10 mL). The reaction was diluted with ether (60mL) and a saturated aqueous solution of sodium bicarbonate (20mL) was added slowly (to slow carbon dioxide gas evolution). sodium thiosulfate (10mL) was then added and stirred at ambient temperature for 30min. the layers were separated and the aqueous layer was extracted with ether (2 × 20 mL.) the combined organics were washed with brine (20mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 2- (1-adamantyl) acetaldehyde as a colorless semi-solid (149 mg, 50%). It was used in the subsequent step without further drying or purification. ¹H NMR (400MHz, benzene-d)₆)9.70(t，J＝3.1Hz，1H)，1.95-1.93(m，1H)，1.89-1.87(m，2H)，1.85(d，J＝ 3.1Hz，2H)，1.68(d，J＝3.0Hz，3H)，1.59(dq，J＝4.0，2.0Hz，2H)，1.56(d，J＝2.2 Hz，1H)，1.49(d，J＝2.8Hz，6H)。

Step 2: n- [2- [2- (1-adamantyl) ethylamino ] ethyl ] carbamic acid tert-butyl ester

To a stirred solution of 2- (1-adamantyl) acetaldehyde (130.0mg, 0.7292mmol) in anhydrous dichloromethane (10mL) was added a solution of tert-butyl N- (2-aminoethyl) carbamate (117mg, 0.7303mmol) in anhydrous dichloromethane (1mL) followed by glacial acetic acid (50. mu.L, 0.8792 mmol) under nitrogen at ambient temperature. The cloudy reaction was stirred for 30min, then sodium triacetoxyborohydride (242mg, 1.142mmol) was added in one portion at ambient temperature and stirring was continued overnight (13 h). Volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (30mL) and washed with saturated aqueous sodium bicarbonate (2X 15mL) and brine (15mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give N- [2- [2- (1-adamantyl) ethylamino) as a yellow gum]Ethyl radical]Tert-butyl carbamate (209mg, 89%). the crude material was used in the next step without further purification ESI-MS M/z calculated 322.26202, experimental 323.4(M +1)⁺(ii) a Retention time: 1.19min (LC method B).

And step 3: 1- [2- (1-adamantyl) ethyl ] imidazolidin-2-one

Solid potassium tert-butoxide (212mg, 1.889mmol) was added to N- [2- [2- (1-adamantyl) ethylamino under nitrogen ]Ethyl radical]Tert-butyl carbamate (200mg, 0.6202mmol) in a stirred solution of anhydrous tetrahydrofuran (12mL) and heating the reaction mixture at 70 ℃ for 13h, allowing the heterogeneous mixture to cool to ambient temperature and acidified with aqueous hydrochloric acid (3.0mL, 1.0M, 3.000mmol) and removing volatiles under reduced pressure, extracting the aqueous residue with ethyl acetate (3 × 10mL) and washing the combined organics with brine (10mL), drying over anhydrous sodium sulfate, filtering and concentrating under reduced pressure, purifying the residue by silica gel chromatography (0% to 10% methanol/dichloromethane gradient over 30min) to give 1- [2- (1-adamantyl) ethyl as an off-white solid]Imidazolidin-2-one (53mg, 34%).¹H NMR (400MHz, benzene-d)₆)4.92(s，1H)3.35-3.25(m, 2H), 2.85-2.76(m, 2H), 2.74-2.66(m, 2H), 1.99(p, J ═ 3.0Hz, 3H), 1.80-1.73(m, 3H), 1.69(dq, J ═ 12.3, 2.3Hz, 3H), 1.55(d, J ═ 2.8Hz, 6H), 1.32-1.21(m, 2H). ESI-MS M/z calculated 248.18886, Experimental 249.3(M +1)⁺(ii) a Retention time: 1.67min (LC method B).

And 4, step 4: (14S) -8- {3- [2- (adamantan-1-yl) ethyl]-2-oxoimidazolidin-1-yl } -12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 228)

Sequentially add (14S) -8-chloro-12, 12-dimethyl-2. lambda. to a 4mL vial⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (20mg, 0.04298mmol), 1- [2- (1-adamantyl) ethyl]Imidazolidin-2-one (13mg, 0.05234mmol), cesium carbonate (52mg, 0.1596mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (4mg, 0.006913 mmol), and anhydrous dioxane (1.0 mL.) nitrogen was bubbled through the heterogeneous mixture for 2min, tris (diphenylmethylidene acetone) dipalladium (0) (4mg, 0.004368mmol) was added under nitrogen and nitrogen was bubbled for an additional 2min, and the reaction capped under a nitrogen atmosphere the mixture was stirred at 115 ℃ overnight, the mixture was cooled to ambient temperature and neutralized with glacial acetic acid (20 μ L, 0.3517mmol), the volatiles were removed under reduced pressure, and the residue was dissolved in dimethyl sulfoxide (1.0mL) and filtered through Whatman 0.45 μm PTFE syringe filter using preparative reverse phase HPLC-MS [ Luna C sold by Phenomenex.₁₈(2) Column (75X 30mm, 5 μm particle size) (pn: 00C-4252-U0-AX), (double gradient run over 15min of 30-99% acetonitrile/water (hydrochloric acid as modifier) ]To purify the sample, (14S) -8- {3- [2- (adamantan-1-yl) ethyl ] ethyl as a yellowish solid]-2-oxoimidazolidin-1-yl } -12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18,23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 228) (13.0mg, 44%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.29(s, 1H), 7.59(d, J ═ 8.6 Hz, 1H), 7.57 to 7.53(m, 1H), 7.41(d, J ═ 8.5Hz, 1H), 7.03(d, J ═ 7.2Hz, 1H), 6.96 (d, J ═ 6.7Hz, 1H), 6.70(d, J ═ 8.5Hz, 1H), 4.00 to 3.82(m, 3H), 3.49 to 3.42(m, 2H), 3.26 to 3.16(m, 2H), 3.13 to 3.03(m, 1H), 2.93(d, J ═ 13.3Hz, 1H), 2.73 to 2.64(m, 1H), 2.18 to 2.01(m, 2H), 1.93(s, 3H), 1.80(d, J ═ 13.3Hz, 1H), 1H), 2.31.51 to 5H, 5(m, 1H), 1H, 5H, 1H, 5H, 1H, 7, 5H, 7, 5H, 1H, 5H, 7, 3H) In that respect ESI-MS M/z calculated 661.341, Experimental 662.5(M +1)⁺(ii) a Retention time: 1.92min (LC method G).

Example 67: preparation of (14S) -8- [3- (adamantan-1-yl) -2-oxoimidazolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 230)

Step 1: n- [2- (1-adamantylamino) ethyl ] carbamic acid tert-butyl ester

To a stirred solution of tert-butyl N- (2-oxoethyl) carbamate (505mg, 3.172mmol) in anhydrous dichloromethane (20 mL) was added solid adamantan-1-amine (hydrochloride) (475mg, 3.141mmol) followed by the sequential addition of triethylamine (500. mu.L, 3.587mmol) and glacial acetic acid (200. mu.L, 3.517mmol), and the reaction was stirred at ambient temperature under nitrogen. The heterogeneous (white suspension) reaction was stirred for 30min, followed by addition of sodium triacetoxyborohydride (1.0g, 4.718mmol) in one portion at ambient temperature and continued stirringOvernight. Volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (30mL) and washed with saturated aqueous sodium bicarbonate (2X 15mL) and brine (15mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give N- [2- (1-adamantylamino) ethyl as a yellow gum]Tert-butyl carbamate (731mg, 79%). ESI-MS M/z calculated 294.23074, Experimental 295.4(M +1)⁺(ii) a Retention time: 0.91min (LC method B).

Step 2: 1- (1-adamantyl) imidazolidin-2-ones

Solid potassium tert-butoxide (465mg, 4.144mmol) was added to N- [2- (1-adamantylamino) ethyl under nitrogen]Tert-butyl carbamate (400mg, 1.359mmol) in a stirred solution of anhydrous tetrahydrofuran (12mL) and the reaction mixture was heated at 70 ℃ for 13 h. The heterogeneous mixture was cooled to ambient temperature and acidified to pH 4-5 with aqueous hydrochloric acid (5.5mL, 1.0M, 5.500mmol) and the volatiles were removed under reduced pressure the aqueous residue was extracted with ethyl acetate (3 × 10mL) and the combined organics were washed with brine (10mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure the residue was purified by silica gel chromatography (0% to 10% methanol/dichloromethane gradient over 30min) to give 1- (1-adamantyl) imidazolidin-2-one as an off-white solid (69mg, 23%).¹H NMR (400MHz, benzene-d)₆)4.91(s, 1H), 2.90(dd, J ═ 8.5, 6.7Hz, 2H), 2.64(ddd, J ═ 8.5, 6.7, 1.2Hz, 2H), 2.21(d, J ═ 2.9Hz, 6H), 2.06(dd, J ═ 5.9, 3.0Hz, 3H), 1.75-1.68(m, 3H), 1.67-1.60(m, 3H). ESI-MS M/z calculated 220.15756, Experimental 221.2(M +1)⁺(ii) a Retention time: 1.36min (LC method B).

And step 3: (14S) -8- [3- (adamantan-1-yl) -2-oxoimidazolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione(Compound 230)

Sequentially add (14S) -8-chloro-12, 12-dimethyl-2. lambda. to a 4mL vial⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (20mg, 0.04298mmol), 1- (1-adamantyl) imidazolidin-2-one (13mg, 0.05901mmol), cesium carbonate (52mg, 0.1596mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (4mg, 0.006913mmol), and anhydrous dioxane (1.0 mL). Nitrogen was bubbled through the heterogeneous mixture for 2 min. Subsequently, tris (dibenzylideneacetone) dipalladium (0) (4mg, 0.004368mmol) was added under nitrogen and nitrogen was bubbled for an additional 2min, and the vial was capped under a nitrogen atmosphere the mixture was stirred at 115 ℃ overnight. The mixture was cooled to ambient temperature and neutralized with glacial acetic acid (20 μ L, 0.3517 mmol). The volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.0mL), filtered through a Whatman 0.45 μm PTFE syringe filter using preparative reverse phase HPLC-MS [ Luna C sold by Phenomenex ₁₈(2) Column (75X 30mm, 5 μm particle size) (pn: 00C-4252-U0-AX), (double gradient run over 15min of 30-99% acetonitrile/water (hydrochloric acid as modifier))]To purify the sample to obtain (14S) -8- [3- (adamantan-1-yl) -2-oxoimidazolidin-1-yl ] as a yellowish solid]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 230) (9mg, 33%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.28(s，1H)，7.61-7.57(m，1H)，7.57-7.52(m，1H)， 7.38(d，J＝8.6Hz，1H)，7.03(d，J＝7.1Hz，1H)，6.96(d，J＝7.3Hz，1H)，6.70(d，J＝ 8.5Hz，1H)，3.96-3.74(m，3H)，3.53-3.46(m，2H)，3.12-3.03(m，1H)，2.93(d，J＝ 13.4Hz，1H)，2.73-2.65(m，1H)，2.12-2.02(m，8H)，1.83-1.71(m，2H)，1.65(s， 5H)，1.62-1.59(m，1H)，1.57(s，3H)，1.55-1.48(m，3H)，1.46(s，3H) 1.36-1.22 (m, 3H). ESI-MS M/z calculated 633.30975, Experimental 634.5(M +1)⁺(ii) a Retention time: 1.66min (LC method G).

Example 68: preparation of (14S) -8- [3- (3, 3-dicyclobutylpropyloxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 231)

Step 1: methanesulfonic acid 2, 2-di (cyclobutyl) ethyl ester

To a 100 mL round bottom flask containing 2, 2-bis (cyclobutyl) ethanol (1.0g, 6.483mmol) in dichloromethane (11.0mL) was added triethylamine (2.72mL, 19.51mmol), the reaction was cooled to 0 deg.C in an ice bath, methanesulfonyl chloride (891mg, 7.778mmol) was added dropwise (exothermic, forming a pale yellowish slurry), and the reaction was stirred for 1h while warming to room temperature after 1h of stirring, the reaction was then quenched with cold water (15mL) (the mixture became a clear pale yellow solution) and extracted twice with dichloromethane (20mL), the organic layer was washed with brine, the organic layer was dried over sodium sulfate, filtered and evaporated, to provide crude 2, 2-bis (cyclobutyl) ethyl methanesulfonate (1.5g, 100%) as a clear colorless to pale yellow liquid. ¹H NMR (400MHz, chloroform-d) 4.03(d, J ═ 4.6Hz, 2H), 2.97(s, 3H), 2.37-2.12(m, 2H), 2.09-1.47(m, 13H).

Step 2: 3, 3-di (cyclobutyl) propionitrile

Under nitrogen atmosphereTo a solution of 2, 2-bis (cyclobutyl) ethyl methanesulfonate (1.75g, 7.532mmol) in dimethyl sulfoxide (23mL) was added solid sodium cyanide (290. mu.L, 9.468 mmol). The mixture was stirred at 70 ℃. Upon heating, the reaction turned to a light yellow slurry, followed by a light amber slurry over time. The reaction was stirred at 70 ℃ for 17h then the reaction mixture was poured into cold water (25mL) and extracted with diethyl ether (3X 25 mL). The combined organic layers were washed with water (2 × 25mL), dried over sodium sulfate, filtered and concentrated to give the crude product 3, 3-bis (cyclobutyl) propionitrile (1.2g, 98%) as a clear light amber liquid, which was used without further purification.¹H NMR (400MHz, chloroform-d) 3.48(q, J ═ 7.0Hz, 1H), 2.38 to 2.21 (m, 2H), 2.10 to 1.92(m, 2H), 1.92 to 1.64(m, 8H), 1.63 to 1.48(m, 2H), 1.21(t, J ═ 7.0Hz, 2H).

And step 3: 3, 3-di (cyclobutyl) propionic acid

To a solution of 3, 3-bis (cyclobutyl) propionitrile (12g, 7.350mmol) in ethanol (18mL) was added sodium hydroxide (12.5mL, 6M, 75.00 mmol). The resulting clear amber solution was heated to 70 ℃ for 3 days. Solid sodium hydroxide (3g, 75.01mmol) was added and the reaction was stirred at 100 ℃ for a further 3 days, ethanol was evaporated and the pH of the aqueous layer was adjusted to 1 with 5M hydrochloric acid. The mixture was then extracted with diethyl ether (3 × 20 mL.) the organic extracts were dried over sodium sulfate, filtered and concentrated to give 3, 3-bis (cyclobutyl) propionic acid (1g, 75%) as a light orange thick oil. ¹H NMR (400MHz, chloroform-d) 2.16(dddd, J ═ 13.0, 9.0, 5.4, 2.5Hz, 2H), 2.10(d, J ═ 6.3Hz, 2H), 1.99-1.87(m, 5H), 1.86-1.60(m, 8H).

And 4, step 4: 3, 3-bis (cyclobutyl) propan-1-ol

Lithium aluminium hydride (300mg, 8.844mmol) (pellets) were suspendedIn tetrahydrofuran (15mL) and stirred at room temperature for 30min, at which time the pellets formed a suspension, then the mixture was cooled in an ice/water bath and tetrahydrofuran (7.2mL) containing 3, 3-bis (cyclobutyl) propionic acid (988mg, 5.421mmol) was added dropwise over 15 min while maintaining the reaction temperature < 20 ℃. the mixture was stirred for 72h in total, allowing it to warm gradually to ambient temperature. The solid was washed with ether. The filtrate was concentrated in vacuo at about 90mbar and 30 ℃ water bath, diluted with diethyl ether, dried (magnesium sulfate), filtered and concentrated in vacuo to give 3, 3-bis (cyclobutyl) propan-1-ol (868mg, 95%) as a colourless liquid. ¹H NMR (400MHz, chloroform-d) 3.64 to 3.54(m, 2H), 2.11(m, J ═ 13.9, 9.8, 7.4, 6.0, 2.0 Hz, 2H), 2.01 to 1.84(m, 4H), 1.83 to 1.59(m, 8H), 1.50 to 1.37(m, 2H).

And 5: 3- [3, 3-bis (cyclobutyl) propoxy ] pyrazole-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 5-oxo-1H-pyrazole-2-carboxylate (530mg, 2.877mmol) and 3, 3-bis (cyclobutyl) propan-1-ol (536mg, 3.185mmol) in tetrahydrofuran (8mL) was added triphenylphosphine (830mg, 3.164mmol). to this mixture was slowly added dropwise diisopropyl azodicarboxylate (680. mu.L, 3.454mmol) over 10 min. the reaction mixture was stirred at 50 ℃ for 16H. The tetrahydrofuran was removed in vacuo toluene was added to the crude mixture to precipitate triphenylphosphine oxide. The thick yellow oil was dissolved in dichloromethane and purified by silica gel chromatography using a gradient of 0% to 20% ethyl acetate/hexanes the pure fractions were combined together and concentrated to dryness to give the desired product, 3- [3, 3-bis (cyclobutyl) propoxy as a white solid]Pyrazole-1-carboxylic acid tert-butyl ester(560mg， 58％).¹H NMR (400MHz, chloroform-d) 7.82(d, J ═ 2.9Hz, 1H), 5.85(d, J ═ 2.9Hz, 1H), 4.21(t, J ═ 7.4Hz, 2H), 2.24-2.11(m, 2H), 2.02-1.86(m, 3H), 1.84-1.64(m, 4H), 1.61(s, 11H), 1.51-1.29(m, 1H). ESI-MS M/z calculated 334.22565, Experimental 335.24(M +1) ⁺(ii) a Retention time: 2.47min (LC method B).

Step 6: 3- [3, 3-bis (cyclobutyl) propoxy ] -1H-pyrazole

To 3- [3, 3-di (cyclobutyl) propoxy group]Pyrazole-1-carboxylic acid tert-butyl ester (200mg, 0.5980mmol) in dichloromethane (2mL) trifluoroacetic acid (700 μ L, 9.086mmol) was added to a solution in dichloromethane (2mL), the mixture was stirred at room temperature for 2h, trifluoroacetic acid was removed under reduced pressure and the resulting crude product was diluted with ethyl acetate, the organic solution was washed with aqueous sodium bicarbonate. The aqueous solution was further extracted with ethyl acetate (2X.) the combined organic layers were dried over sodium sulfate, filtered, and concentrated to dryness to give 3- [3, 3-di (cyclobutyl) propoxy group]ESI-MS M/z calculated 234.17322, Experimental 235.15(M +1)⁺(ii) a Retention time: 1.9min (LC method B).

And 7: 2-chloro-6- [3- [3, 3-di (cyclobutyl) propoxy ] pyrazol-1-yl ] pyridine-3-carboxylic acid tert-butyl ester

Tert-butyl 2, 6-dichloropyridine-3-carboxylate (275mg, 1.108mmol) and 3- [3, 3-di (cyclobutyl) propoxy]-1H-pyrazole (260mg, 1.110mmol) and potassium carbonate (185mg, 1.339mmol) were combined in anhydrous dimethylsulfoxide (5.2 mL). Addition of 1, 4-diazabicyclo [2.2.2]Octane (25mg, 0.2229mmol) and the mixture was stirred at room temperature under nitrogen for 16h, the reaction mixture was diluted with water (10mL) and stirred for 15min, the resulting white solid was collected and washed with water. The solid was dissolved in dichloromethane and dried over magnesium sulfate. The mixture was filtered and evaporated to dryness, The product 2-chloro-6- [3- [3, 3-di (cyclobutyl) propoxy ] is obtained as a colorless oil]Pyrazol-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (367mg, 74%).¹H NMR (400MHz, chloroform-d) 8.35(d, J ═ 2.9Hz, 1H), 8.18(d, J ═ 8.4Hz, 1H), 7.69(d, J ═ 8.4Hz, 1H), 5.95(d, J ═ 2.8Hz, 1H), 4.20(t, J ═ 7.5Hz, 2H), 2.18(tt, J ═ 9.6, 4.4Hz, 2H), 2.07-1.86(M, 4H), 1.87-1.35 (M, 20H), ESI-MS M/z calculated 445.21323, experimental 446.29(M +1)⁺(ii) a Retention time: 0.88min (LC method L).

And 8: 2-chloro-6- [3- [3, 3-di (cyclobutyl) propoxy ] pyrazol-1-yl ] pyridine-3-carboxylic acid

2-chloro-6- [3- [3, 3-di (cyclobutyl) propoxy group]Pyrazol-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (367mg, 0.8229mmol) was dissolved in dichloromethane (4mL) and trifluoroacetic acid (1.5mL, 19.47mmol) was added the reaction was stirred at room temperature for 16h the reaction was evaporated and the resulting solid was suspended in ether and the ether was then removed under reduced pressure. This evaporation from the ether procedure was repeated twice to yield 2-chloro-6- [3- [3, 3-di (cyclobutyl) propoxy ] as a white solid]Pyrazol-1-yl]Pyridine-3-carboxylic acid (300mg, 94%). ESI-MS M/z calculated 389.1506, Experimental 390.22(M +1) ⁺(ii) a Retention time: 1.45min (LC method J).

And step 9: (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [3, 3-di (cyclobutyl) propoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

In a 20mL scintillation vial, 2-chloro-6- [3- (3, 3-di (cyclobutyl) propoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (71mg, 0.1821mmol) and carbonyldiimidazole (30mg, 0.1850mmol) were combined in tetrahydrofuran (550. mu.L) and stirred at 50 ℃ for 60min with a loose lid, then (4S) -2, 2-bis-containing solution was addedMethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino group]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (50mg, 0.1212mmol) in tetrahydrofuran (850 μ L) followed by the addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (36 μ L, 0.2407mmol) and the reaction was heated at 50 ℃ for 16 h. The reaction mixture was cooled to room temperature and then concentrated to an oily residue which was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution followed by brine the organics were separated, dried over sodium sulfate, filtered and evaporated, then purified by silica gel chromatography using a gentle gradient of 100% dichloromethane to 20% methanol/dichloromethane to give (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [3, 3-di (cyclobutyl) propoxy ] as a light yellow thick oil ]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (64.5mg, 66%). ESI-MS M/z calculated 783.3545, Experimental value 784.46(M +1)⁺(ii) a Retention time: 2.21min (LC method J).

Step 10: 2-chloro-6- [3- [3, 3-bis (cyclobutyl) propoxy ] pyrazol-1-yl ] -N- [ [6- [3- [ (3s) -5, 5-dimethylpyrrolidin-3-yl ] propylamino ] -2-pyridinyl ] sulfonyl ] pyridine-3-carboxamide (trifluoroacetate)

Reacting (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [3, 3-di (cyclobutyl) propoxy ] group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (64.5mg, 0.082 mmol) was dissolved in dichloromethane (1.5 mL.) trifluoroacetic acid (235 μ L, 3.050mmol) was added and the resulting reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure and the resulting crude product was further dried under high vacuum to give 2-chloro-6- [3- [3, 3-di (cyclobutyl) propoxy group]Pyrazol-1-yl]-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] radical]Propylamino group]-2-pyridyl]Sulfonyl radical]Pyridine-3-carboxamide (trifluoroacetate salt) (53mg, 52%, 97% purity). ESI-MS M/z calculated 683.30206, Experimental 684.39(M +1) ⁺(ii) a Retention time: 0.86min (LC method J).

Step 11: (14S) -8- [3- (3, 3-dicyclobutylpropyloxy) -1H-pyrazol-1-yl radical]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 231)

2-chloro-6- [3- [3, 3-di (cyclobutyl) propoxy group]Pyrazol-1-yl]-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] radical]Propylamino group]-2-pyridyl]Sulfonyl radical]Pyridine-3-carboxamide (trifluoroacetate) (52mg, 0.07599mmol), potassium carbonate (55mg, 0.3980mmol), cesium fluoride (25mg, 0.1646mmol),

A mixture of molecular sieves and dimethylsulfoxide (3.6mL) was placed in a vial, purged with nitrogen, capped, heated to 165 deg.C and stirred for 16h₁₈(2) The filtrate was purified by double gradient running of a column (75 × 30mM, 5 μm particle size) (pn: 00C-4252-U0-AX) and 30-99% mobile phase B over 15.0min (mobile phase a ═ water (5 mM hydrochloric acid), mobile phase B ═ acetonitrile, flow rate 50mL/min, injection volume 1300 μ L and column temperature 25 ℃) to give (14S) -8- [3- (3, 3-dicyclobutylpropyloxy) -1H-pyrazol-1-yl as a white solid ]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 231) (15.5mg, 32%).¹H NMR (400 MHz, chloroform-d) 9.96(s, 1H), 8.19(d, J ═ 2.8Hz, 1H), 8.07(d, J ═ 8.4Hz, 1H), 7.60-7.48 (m, 2H), 7.28(d, J ═ 8.3Hz, 1H), 6.56(dd, J ═ 8.1, 1.1Hz, 1H), 5.91(d, J ═ 2.8Hz, 1H), 4.70(d, J ═ 7.0Hz, 1H), 4.20(t, J ═ 7.4Hz, 2H), 3.90(s, 1H), 3.35(dd, J ═ 10.1, 7.5Hz, 1H), 3.17(d, J ═ 14.1Hz, 1H), 3.8 (t, 8H), 9.8H, 1H), 1H, 7.17 (d, J ═ 14.06, 1H), 3.06, 1H), 3.6, 1H, 1) 2.26-2.11(m, 2H), 2.09(dd, J ═ 12.3, 7.9Hz, 1H), 2.03-1.86(m, 3H), 1.80(s, 1H), 1.82-1.72(m, 2H), 1.76-1.62(m, 3H), 1.62(d, J ═ 3.3Hz, 7H), 1.46(ddd, J ═ 14.2, 9.0, 5.2Hz, 1H), 1.26(s, 1H), several aliphatic protons are masked by the water peak. ESI-MS M/z calculated 647.3254, Experimental 648.38(M +1)⁺(ii) a Retention time: 1.89min (LC method J).

Example 69: preparation of 7, 7-dimethyl-11- (3- {3- [1- (trifluoromethyl) cyclopropyl [ ]]Propoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14 ]Tricosano-1 (22), 9, 11, 13, 18, 20-hexaen-15, 17, 17-trione (enantiomer 1) (compound 234) and 7, 7-dimethyl-11- (3- {3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosano-1 (22), 9, 11, 13, 18, 20-hexaene-15, 17, 17-trione (enantiomer 2) (compound 235)

Step 1: 3- (2-methyl-2-nitropropyl) -dihydrofuran-2-one

To 2-nitropropane (49mL, 2.2mol) and 1, 8-diazabicyclo [5.4.0 ] over a 45min period under a nitrogen atmosphere]To a mixture of undec-7-ene (4.1mL, 0.1mol) was added 3-methylenedihydrofuran-2 (3H) -one (75g, 776mmol) dropwise. The addition was exothermic: the temperature was kept below 90 ℃ by controlling the addition rate during the course of the reaction. The mixture was stirred at 85 ℃ for an additional 4h, cooled to room temperature and diluted with ethyl acetate (500mL) and 1M hydrochloric acid (60 mL). The organic phase was separated, dried over sodium sulfate, filtered and concentrated in vacuo to afford a dark oil. Trituration with a small amount of methyl tert-butyl ether produced a large amount of white precipitate which was collected by filtrationThe precipitate was colored to give 3- (2-methyl-2-nitropropyl) -dihydrofuran-2-one as a white solid (75.6g, 73% yield). The material was used in the next step without further purification ESI-MS M/z calculated 187.2, experimental 188.0(M +1) ⁺(ii) a Retention time: 2.34min (LC method M).

Step 2: 3- (2-hydroxyethyl) -5, 5-dimethylpyrrolidin-2-one

A 1.5 litre balm reactor was charged with raney nickel slurry (10g), 3- (2-methyl-2-nitropropyl) -dihydrofuran-2-one (75.6g, 0.86mol) and ethanol (1.2L), the reactor was sealed and heated to 60 ℃ under 2 barg of hydrogen for 16h and then cooled to room temperature approximately 100g of diatomaceous earth was added to the reactor. The resulting slurry was filtered through a thin silica gel pad and rinsed with ethanol (200 mL.) the combined filtrates were concentrated in vacuo to give 3- (2-hydroxyethyl) -5, 5-dimethylpyrrolidin-2-one (64.5g, quantitative yield) as a white solid, the crude material was used in the next step without further purification ESI-MS M/z calculated 157.2, experimental 158.1 (M +1)⁺(ii) a Retention time: 1.38min (LC method M).

And step 3: (4- (2-hydroxyethyl) -2, 2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester

Lithium aluminum hydride (53.9g, 1.4mol) was added to a mixture of 3- (2-hydroxyethyl) -5, 5-dimethylpyrrolidin-2-one (55.8 g, 0.36mol) and tetrahydrofuran (710mL) over a 45min period in small portions to avoid excessive hydrogen evolution. The mixture was refluxed for 22h under a nitrogen atmosphere the mixture was cooled to room temperature and carefully quenched by addition of sodium sulfate decahydrate (300g), the resulting grey slurry was filtered and the solids were washed with tetrahydrofuran (500 mL), tert-butyl dicarbonate (52.3g, 225mmol) was added to the combined filtrate (1.2L). The resulting mixture was stirred at room temperature for 24 h. Mixing the reaction mixture Concentration and purification by silica gel chromatography using a 0% to 100% gradient of ethyl acetate/hexanes to give tert-butyl (4- (2-hydroxyethyl) -2, 2-dimethylpyrrolidine-1-carboxylate (40.8g, 74% yield) as a pale oil, calculated as ESI-MS M/z 243.3, experimental 244.1 (M +1)⁺(ii) a Retention time: 4.01min (LC method M).

And 4, step 4: 4- (2-Methanesulfonyloxyethyl) -2, 2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester

Tert-butyl 4- (2-hydroxyethyl) -2, 2-dimethylpyrrolidine-1-carboxylate (32.1g, 132mmol) and triethylamine (36.8mL, 264mmol) were dissolved in dichloromethane (400mL) and the resulting mixture was cooled in an ice-water bath for 15 min. Methanesulfonyl chloride (11.3mL, 145mmol) was added dropwise and the reaction was stirred for 30min. the reaction was quenched by addition of saturated aqueous sodium bicarbonate solution (100 mL.) the organic layer was separated, washed with water (100mL), dried over sodium sulfate, filtered and concentrated to give tert-butyl 4- (2-methanesulfonyloxyethyl) -2, 2-dimethylpyrrolidine-1-carboxylate (41.6g, 98% yield) as an orange oil which was used in the next step without further purification ESI-MS M/z calculated 321.4, experimental 322.2(M +1)⁺(ii) a Retention time: 4.88min (LC method M).

And 5: 4- (2-aminoethyl) -2, 2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester

A 1.5 liter balm reactor was charged with 4- (2-methanesulfonyloxyethyl) -2, 2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester (32.4g, 101mmol), dioxane (640mL), and 30% ammonium hydroxide (640mL)The phases were separated, the aqueous phase was extracted with dichloromethane (2 × 250mL) and discarded, the combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography using a 0% to 15% methanol/dichloromethane gradient containing 5 ml/l of 30% ammonium hydroxide to give tert-butyl 4- (2-aminoethyl) -2, 2-dimethylpyrrolidine-1-carboxylate as a pale oil (20.6g, 66% yield).¹H NMR(500MHz，CDCl₃) (ppm): 3.66(dt, 1H), 2.88(p, 1H), 2.69(m, 2H), 2.15(m, 1H), 1.88(m, 1H), 1.48-1.14(m, 20H). ESI-MS M/z calculated 242.3, Experimental 243.0(M +1)⁺(ii) a Retention time: 3.06min (LC method M).

Step 6: 2, 2-dimethyl-4- [2- [ (6-sulfamoyl-2-pyridyl) amino ] ethyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

To a 20mL microwave vessel were added 6-fluoropyridine-2-sulfonamide (2.089g, 11.86mmol) and dimethyl sulfoxide (24 mL). Potassium carbonate (8.60g, 62.23mmol) and tert-butyl 4- (2-aminoethyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (3.00g, 12.38mmol) were added and the vial was capped and heated to 100 ℃ on a hot plate for 4 h. The organic layer was separated, dried over sodium sulfate, filtered and evaporated, then purified by silica gel chromatography using a gradient of 100% hexane to 80% ethyl acetate/hexane to give 2, 2-dimethyl-4- [2- [ (6-sulfamoyl-2-pyridyl) amino group as a white solid]Ethyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (1.475 g, 31%). ESI-MS M/z calculated 398.19876, Experimental value 399.2(M +1)⁺(ii) a Retention time: 1.55 min (LC method B).

And 7: 4- [2- [ [6- [ [ 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] ethyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

Adding 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] to a round bottom flask]Propoxy group ]Pyrazol-1-yl]Pyridine-3-carboxylic acid (361mg, 0.9262mmol) and newly recrystallized carbonyldiimidazole (188mg, 1.159mmol). tetrahydrofuran (5.5mL) was added and the reaction was heated at 40 ℃ for 2h 2, 2-dimethyl-4- [2- [ (6-sulfamoyl-2-pyridyl) amino]Ethyl radical]A solution of pyrrolidine-1-carboxylic acid tert-butyl ester (370mg, 0.9284mmol) in tetrahydrofuran (2mL) was added followed by 1, 8-diazabicyclo [5.4.0]Undec-7-ene (450 μ L, 3.009 mmol.) the reaction turned light yellow and was stirred at room temperature overnight. The reaction was quenched with saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude residue was then purified by silica gel chromatography using a gradient of 0% to 100% ethyl acetate/hexane to give 4- [2- [ [6- [ [ 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] propyl ] as a white foam]Propoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Ethyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (400mg, 56%). ESI-MS M/z calculated 769.2636, Experimental 770.4(M +1)⁺(ii) a Retention time: 2.01min (LC method G).

And 8: 2-chloro-N- [ [6- [2- (5, 5-dimethylpyrrolidin-3-yl) ethylamino ] -2-pyridinyl ] sulfonyl ] -6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carboxamide

To a solution containing 4- [2- [ [6- [ [ 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] group]Propoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Ethyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (400 mg, 0.5193mmol) in a round bottom flask was added dichloromethane (10mL) and trifluoroacetic acid (2.0mL, 25.96 mmol) the reaction was stirred at room temperature for 90min then evaporated to dryness. The crude reaction mixture was neutralized with saturated sodium bicarbonate and washed with waterThe organic layer was separated (dried over sodium sulfate) and evaporated to provide 2-chloro-N- [ [6- [2- (5, 5-dimethylpyrrolidin-3-yl) ethylamino ] as a white solid]-2-pyridyl]Sulfonyl radical]-6- [3- [3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxamide (344mg, 99%). ESI-MS M/z calculated 669.2112, Experimental 670.5(M +1)⁺(ii) a Retention time: 0.94min (LC method G).

And step 9: 7, 7-dimethyl-11- (3- {3- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Propoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosano-1 (22), 9, 11, 13, 18, 20-hexaene-15, 17, 17-trione (Compound 233)

To a microwave vial was added potassium carbonate (355mg, 2.569mmol), cesium fluoride (156mg, 1.027 mmol), several

Molecular sieves and 2-chloro-N- [ [6- [2- (5, 5-dimethylpyrrolidin-3-yl) ethylamino]-2-pyridyl]Sulfonyl radical]-6- [3- [3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]A solution of pyridine-3-carboxamide (344mg, 0.5133mmol) in dimethylsulfoxide (4 mL). The reaction was capped and placed in a preheated 150 ℃ oil bath overnight. The reaction was cooled to room temperature, filtered and purified by HPLC, gradient of 50% -99% acetonitrile in water (0.1% hydrochloric acid modifier) to give 7, 7-dimethyl-11- (3- {3- [1- (trifluoromethyl) cyclopropyl as a white powder]Propoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosane-1 (22), 9, 11, 13, 18, 20-hexaene-15, 17, 17-trione (compound 233) (138.6mg, 43%). ESI-MS M/z calculated 633.2345, Experimental 634.3(M +1)⁺(ii) a Retention time: 2.22min (LC method B).

Step 10: 7, 7-dimethyl-11- (3-)3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14 ]Tricosano-1 (22), 9, 11, 13, 18, 20-hexaen-15, 17, 17-trione (enantiomer 1) (compound 234) and 7, 7-dimethyl-11- (3- {3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosano-1 (22), 9, 11, 13, 18, 20-hexaene-15, 17, 17-trione (enantiomer 2) (compound 235)

Racemic 7, 7-dimethyl-11- (3- {3- [1- (trifluoromethyl) cyclopropyl ] rac-7, 7-dimethyl-11- (3- {3- [1- (trifluoromethyl) cyclopropyl ] chromatography using ChiralPak AS-H (250X 21.2mm column, 5 μm particle size) and 28% acetonitrile: methanol (90: 10; no modifier)/72% carbon dioxide mobile phase (70mL/min)]Propoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Distrideca-1 (22), 9, 11, 13, 18, 20-hexaen-15, 17, 17-trione (compound 233) (138.6mg, 0.2187mmol) was isolated to give 7, 7-dimethyl-11- (3- {3- [1- (trifluoromethyl) cyclopropyl ] as the first enantiomer to be eluted]Propoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosane-1 (22), 9, 11, 13, 18, 20-hexaene-15, 17, 17-trione (enantiomer 1) (compound 234) (68.1mg, 98%). ESI-MS M/z calculated 633.2345, Experimental 634.4(M +1) ⁺(ii) a Retention time: 2.22min (LC method B.) the second enantiomer to be eluted was 7, 7-dimethyl-11- (3- {3- [1- (trifluoromethyl) cyclopropyl ] methyl]Propoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosane-1 (22), 9, 11, 13, 18, 20-hexaene-15, 17, 17-trione (enantiomer 2) (compound 235) (59.3mg, 86%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.46(s，1H)，8.20(d，J＝2.8 Hz，1H)，7.75(d, J ═ 33.8Hz, 2H), 7.18(s, 1H), 6.90(d, J ═ 8.2Hz, 1H), 6.82(s, 1H), 6.11(d, J ═ 2.8Hz, 1H), 4.20(t, J ═ 6.2Hz, 2H), 3.72-3.46(m, 1H), 2.26(s, 1H), 1.99-1.65(m, 6H), 1.55(s, 6H), 1.49-1.15(m, 2H), 0.95-0.87(m, 2H), 0.79-0.70 (m, 2H), some of which are masked by the solvent. ESI-MS M/z calculated 633.2345, Experimental 634.3 (M +1)⁺(ii) a Retention time: 2.22min (LC method B).

Example 70: preparation of (14S) -12, 12-dimethyl-8- [ 2-oxo-3- (4, 4, 4-trifluoro-3, 3-dimethylbutoxy) pyrrolidin-1-yl]-2λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [ [17.3.1.111, 14.05, 10 ]]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 237)

Step 1: 3- (4, 4, 4-trifluoro-3, 3-dimethyl-butoxy) pyrrolidin-2-one

To a stirred solution of 4, 4, 4-trifluoro-3, 3-dimethyl-butan-1-ol (280mg, 1.793mmol, containing 29 mol% residual diethyl ether) and 3-bromopyrrolidin-2-one (275mg, 1.677mmol) in anhydrous tetrahydrofuran (12mL) at-50 ℃ to-60 ℃ over 2min under nitrogen was added [ bis (trimethylsilyl) amino]Potassium (7.1 mL, 0.5M in toluene, 3.550 mmol.) after stirring at this temperature for 15min, the cooling bath was removed and the flask was immediately placed in an ice-water bath at 0 ℃. The reaction was then allowed to warm to ambient temperature and stirring was continued overnight under nitrogen. Glacial acetic acid (200 μ L, 3.517mmol) was added to the reaction and volatiles were removed under reduced pressure the residue was purified by silica gel chromatography (gradient 0% to 10% methanol/dichloromethane over 25min) to give 3- (4, 4, 4-trifluoro-3, 3-dimethyl-butoxy) pyrrolidin-2-one as an off-white solid (238mg, 59%).¹H NMR (400MHz, benzene-d)₆)5.87(s，1H) 4.13(dt, J ═ 9.6, 7.0Hz, 1H), 3.42(dt, J ═ 9.6, 6.8Hz, 1H), 3.39-3.33(m, 1H), 2.52-2.41(m, 1H), 2.25(dt, J ═ 9.6, 7.0Hz, 1H), 1.72(td, J ═ 6.9, 1.5Hz, 2H), 1.57-1.43(m, 2H), 0.94(d, J ═ 3.6Hz, 6H). 19F NMR (376MHz, benzene-d 6) -78.62 ESI-MS M/z calculated 239.11331, experimental 240.2(M +1) ⁺(ii) a Retention time: 1.16min (LC method B).

Step 2: (14S) -12, 12-dimethyl-8- [ 2-oxo-3- (4, 4, 4-trifluoro-3, 3-dimethylbutoxy) pyrrolidin-1-yl]-2λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 237)

Sequentially add (14S) -8-chloro-12, 12-dimethyl-2. lambda. to a 4mL vial⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (20mg, 0.04445mmol), 3- (4, 4, 4-trifluoro-3, 3-dimethyl-butoxy) pyrrolidin-2-one (13mg, 0.05434 mmol), cesium carbonate (52mg, 0.1596mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (4mg, 0.006913mmol) and anhydrous dioxane (0.7mL), nitrogen was purged through the heterogeneous mixture for 3 min, then tris (benzylidene acetone) dipalladium (0) (4mg, 0.004368mmol) was added under nitrogen and again purged through the mixture for 2min and capped under nitrogen atmosphere, the mixture was stirred at 108 ℃ overnight, the mixture was cooled to ambient temperature and treated with glacial acetic acid (20 μ L, 0.3517mmol) was removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.5mL) and filtered through a Whatman 0.45 μm PTFE syringe filter using preparative reverse phase HPLC-MS [ Luna C sold by Phenomenex ₁₈(2) Column (75X 30mm, 5 μm particle size) (pn: 00C-4252-U0-AX), run for 15min with double gradient of 30% -99% acetonitrile/water (hydrochloric acid as modifier)]Purifying the sample to obtain (14S) -12 as a yellowish solid,12-dimethyl-8- [ 2-oxo-3- (4, 4, 4-trifluoro-3, 3-dimethylbutoxy) pyrrolidin-1-yl]-2λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 237) (8mg, 27%).¹H NMR (400 MHz, dimethylsulfoxide-d)₆)12.42(s, 1H), 7.71(dd, J ═ 8.4, 1.9Hz, 1H), 7.57(dd, J ═ 8.5, 7.2Hz, 1H), 7.52(dd, J ═ 8.4, 6.3Hz, 1H), 7.04(dt, J ═ 7.3, 0.9Hz, 1H), 6.96(d, J ═ 8.8Hz, 1H), 6.70(dd, J ═ 8.5, 0.8Hz, 1H), 4.31 (two t, J ═ 8.3Hz, 1H), 4.08-3.87 (m, 3H), 3.81-3.64(m, 2H), 3.17-3.04(m, 1H), 2.94(d, J ═ 13.2, 1H), 2.63-2H, 1.73 (dd, 1.4, 1.2H), 1.47, 1.82 (1H), 1H, 2H, 1H, 2H, 1H, 2H, 1, 3H) 1.50(t, J ═ 12.4Hz, 1H), 1.46(s, 3H), 1.29(dd, J ═ 13.6, 12.8Hz, 1H), 1.14(t, J ═ 1.9Hz, 6H). ¹⁹F NMR (376MHz, dimethylsulfoxide-d)₆) -77.59. ESI-MS M/z calculated 652.2655, Experimental 653.4(M +1)⁺(ii) a Retention time: 2.1min (LC method B).

Example 71: preparation of 12, 12-dimethyl-8- {3- [ 3-methyl-2- (prop-2-yl) butoxy]-1H-pyrazol-1-yl } -15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 238)

Step 1: 4- [2- [ [6- [ [ 2-chloro-6- [3- (2-isopropyl-3-methyl-butoxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] ethoxy ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- (2-isopropyl-3-methyl-butoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (225mg, 0.6395 mmol) and carbonyldiimidazole (111mg, 0.6846mmol) were combined in dry tetrahydrofuran (8mL) and stirred at 40 ℃ for 75 min. Followed by addition of 2, 2-dimethyl-4- [2- [ (6-sulfamoyl-2-pyridyl) amino]Ethoxy radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (265mg, 0.6393mmol) and 1, 8-diazabicyclo [5.4.0]A solution of undec-7-ene (200. mu.L, 1.337mmol) in tetrahydrofuran (7 mL). The reaction was heated at 50 ℃ for 4h, diluted with ethyl acetate and washed with 1M citric acid solution followed by brine the organics were separated, dried over sodium sulfate, filtered and evaporated and then purified by silica gel chromatography using a gradient of 100% hexane to 75% ethyl acetate/hexane to give 4- [2- [ [6- [ [ 2-chloro-6- [3- (2-isopropyl-3-methyl-butoxy) pyrazol-1-yl as an off-white solid ]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Ethoxy radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (176mg, 37%). ESI-MS M/z calculated 747.3181, Experimental 748.41 (M +1)⁺(ii) a Retention time: 0.67min (LC method A).

Step 2: 12, 12-dimethyl-8- {3- [ 3-methyl-2- (prop-2-yl) butoxy]-1H-pyrazol-1-yl } -15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 238)

Reacting 4- [2- [ [6- [ [ 2-chloro-6- [3- (2-isopropyl-3-methyl-butoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Ethoxy radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (176mg, 0.2352 mmol) was dissolved in dichloromethane (3mL) and trifluoroacetic acid (550 μ L, 7.14 mmol) was added to the mixture, the reaction solution was stirred at room temperature for 30min, the reaction mixture was concentrated to dryness under reduced pressure, the resulting residue was taken up with potassium carbonate (195mg, 1.41mmol), cesium fluoride (53.6mg, 0.353mmol),

Molecular sieves and dimethylsulfoxide (3mL) were combined in a vial and purged with nitrogen the vial was capped, heated to 140 ℃ and stirred for 20 h. The reaction mixture was cooled to room temperature, filtered and then subjected to reverse-phase preparative chromatography (C) ₁₈Column, 30% to 99% acetonitrile (no modifier) in water (5mM hydrochloric acid) for 30min) to give 12, 12-dimethyl-8- {3- [ 3-methyl-2- (propan-2-yl) butoxy as a white solid]-1H-pyrazol-1-yl } -15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 238) (64mg, 44%).¹H NMR (400 MHz, dimethylsulfoxide-d)₆)12.59(s, 1H), 8.20(d, J ═ 2.8Hz, 1H), 7.79(d, J ═ 8.2Hz, 1H), 7.59(dd, J ═ 8.5, 7.2Hz, 1H), 7.13(d, J ═ 9.1Hz, 1H), 7.10(d, J ═ 7.2Hz, 1H), 6.96 (d, J ═ 8.2Hz, 1H), 6.71(d, J ═ 8.5Hz, 1H), 6.11(d, J ═ 2.8Hz, 1H), 4.23(d, J ═ 4.8 Hz, 2H), 4.10(d, J ═ 8.7Hz, 2H), 3.88(t, J ═ 11.9, 1H), 3.61(d, J ═ 12.8 Hz, 2H), 4.10(d, J ═ 8.7Hz, 2H), 3.88(t, J ═ 11.9, 1H), 3.7, 7H, 7(d, 7, 1.9H), 6.9, 7H, 1H, 9H, 1H), 7H, 1H, 9(d, 1H, 9, 1H), 6.9, 1H, 9H, 1H, 7H), 6.9H, 7H, 1H, 9H), 7H, 9H, 1H, 9H, 1H, 7H, 1H, 9H, 0.98(d, J ═ 6.8Hz, 6H), 0.92(d, J ═ 6.8Hz, 6H). ESI-MS M/z calculated 611.289, Experimental 612.2(M +1) ⁺(ii) a Retention time: 2.29min (LC method B).

Example 72: preparation of (14S) -8- {3- [2- (adamantan-1-yl) ethoxy]-2-oxopyrrolidin-1-yl } -12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 240) and (14S) -8- {3- [2- (adamantan-1-yl) ethoxy]-2-oxopyrrolidin-1-yl } -12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 241)

Step 1: 3- [2- (1-adamantyl) ethoxy ] pyrrolidin-2-one

To a solution of 1-adamantaneethanol (1.099g, 6.098mmol) and 3-bromopyrrolidin-2-one (1.00g, 6.098mmol) in anhydrous tetrahydrofuran (50mL) was added dropwise potassium bis (trimethylsilyl) amide (1.0M in tetrahydrofuran, 12.8mL, 12.8mmol) at-50 ℃. The reaction was stirred at the same temperature for 20min, then in an ice bath for 3h the reaction was quenched with saturated aqueous ammonium chloride (50mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was triturated with hexanes and the solid formed was collected by filtration to give 3- (2-adamantan-1-yl-ethoxy) -pyrrolidin-2-one as an off-white solid (1.192g, 74%). ¹H-NMR (250MHz, dimethylsulfoxide-d)₆) d (ppm): 7.78(s, br, 1H), 3.81(M, 2H), 3.51(q, t ═ 8.8Hz, 1H), 3.11 (M, 2H), 2.27(M, 1H), 1.90-1.40(M, 16H), 1.30(t, J ═ 7.3Hz, 2H), ESI-MS M/z calculated 263.19, experimental 263.8(M +1)⁺(ii) a Retention time: 5.24min (LC method Q).

Step 2: (14S) -8- {3- [2- (adamantan-1-yl) ethoxy]-2-oxopyrrolidin-1-yl } -12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 240) and (14S) -8- {3- [2- (adamantan-1-yl) ethoxy]-2-oxopyrrolidin-1-yl } -12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 241)

A4 mL vial was charged with (14S) -8-chloro-12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (35mg, 0.07779 mmol), 3- [2- (1-adamantyl) ethoxy ]Pyrrolidin-2-one (29mg, 0.1101mmol), Pd₂(dba)₃(11 mg, 0.01201mmol), xanthphos (9mg, 0.01555mmol), cesium carbonate (129mg, 0.3959mmol) and anhydrous dioxane (0.5 mL). The mixture was sparged with nitrogen for about 3min, capped and stirred at 120 ℃ for 14 h. The organic solvent was concentrated by blowing nitrogen into the vial. The residue was diluted with dimethyl sulfoxide (900 μ L), microfiltered and subjected to reverse phase preparative HPLC (C) using a gradient of acetonitrile in water (30 to 99% over 15min) and hydrochloric acid as modifier (cl;)₁₈) The pure fractions were collected and the organic solvent was evaporated. The resulting aqueous solution was extracted with dichloromethane (1 ×) and ethyl acetate (2 ×), and the organic phases were combined and dried over sodium sulfate. Filtration followed by evaporation of the solvent gave a solid which was further purified by flash chromatography on silica gel using a gradient of methanol in dichloromethane (0% to 5% over 30 min.) the pure fractions were combined and the solvent was evaporated. The residue was triturated with dichloromethane/hexane and the solvent evaporated to give a mixture of diastereomers which was passed over chiral SFC (chiralCel OJ-H (250X 10mM), 5. mu.M column; mobile phase: 24% acetonitrile/methanol (90: 10, 20 mM NH)₃) 76% carbon dioxide, 10 mL/min; 14mg/mL in acetonitrile: methanol: dimethyl sulfoxide (81: 9: 10); injection volume 70 μ L, 100 bar).

The first diastereomer to elute was (14S) -8- {3- [2- (adamantan-1-yl) ethoxy]-2-oxopyrrolidin-1-yl } -12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 240) (6.1 mg, 22%, 98% ee).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.45 (width s, 1H), 7.69(d, J ═ 8.4Hz, 1H), 7.60-7.44(m, 2H), 7.03(d, J ═ 7.2Hz, 1H), 6.94(br s, 1H), 6.68(br d, J ═ 8.5Hz, 1H), 4.21(t, J ═ 8.0Hz, 1H), 4.02(t, J ═ 9.5Hz, 1H), 3.97-3.82(m, 2H), 3.74-3.65(m, 1H), 3.64-3.53(m, 1H), 3.12(br s, 1H), 2.93(d, J ═ 13.3Hz, 1H), 2.77-2.64(m, 1H), 2.45-2.34(m, 1H), 2.03-2.31H (m, 1H), 2.19-1H, 1H), 1.71-6.5 (m, 1H), 1H, 6.6-3.5 (m, 1H). ESI-MS M/z calculated 676.3407, Experimental 677.4(M +1)⁺(ii) a Retention time: 2.42min (LC method B.) the second diastereomer to be eluted was (14S) -8- {3- [2- (adamantan-1-yl) ethoxy]-2-oxopyrrolidin-1-yl } -12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 242) (5.1mg, 17%, 93% ee).¹H NMR (400 MHz, dimethylsulfoxide-d)₆)12.44 (width s, 1H), 7.70(d, J ═ 8.4Hz, 1H), 7.61-7.49(M, 2H), 7.04(d, J ═ 7.2Hz, 1H), 7.00-6.89(br M, 1H), 6.70(d, J ═ 8.5Hz, 1H), 4.26(t, J ═ 8.2Hz, 1H), 3.98-3.82(M, 3H), 3.76(q, J ═ 8.5Hz, 1H), 3.58(q, J ═ 7.7Hz, 1H), 3.10(br s, 1H), 2.94(br d, J ═ 13.3Hz, 1H), 2.74-2.63(M, 1H), 2.47-2.34(M, 1H), 2.10(br d, 1H), 2.68 (br d, J ═ 13.3Hz, 1H), 2.74-2.63(M, 1H), 19 (M, 19, 1H), 19, 1H, 18M-19 (M, 1H), calculated values (M, 1H), 1H, 18, 1H⁺(ii) a Retention time: 2.41min (LC method B).

Example 73: preparation of (14S) -12, 12-dimethyl-8- (2-oxo-3- {3- [1- (trifluoromethyl) cyclopropyl]Propoxy pyrrolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 242) and (14S) -12, 12-dimethyl-8- (2-oxo-3- {3- [1- (trifluoromethyl) cyclopropyl ]Propoxy pyrrolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer)Isomer 2) (Compound 243)

Step 1: 3- [3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrrolidin-2-one

A100 mL flask was charged with 3- [1- (trifluoromethyl) cyclopropyl ] under nitrogen]Propan-1-ol (450mg, 2.676mmol), 3-bromopyrrolidin-2-one (442mg, 2.695mmol) and anhydrous tetrahydrofuran (12mL). (iv) dropwise addition of [ bis (trimethylsilyl) amino ] over 5min]Potassium (11.3mL, 0.5M in toluene, 5.650mmol) and the yellow mixture was stirred at-50 ℃ for 15-20min, followed by stirring in an ice bath at 0 ℃ for at least 3h the reaction was stirred in an ice bath, slowly warming to room temperature. After 16h, the mixture was cooled to 0 ℃ and glacial acetic acid (250 μ L, 4.396mmol) was added to the reaction to give a light brown slurry. Brine (75mL) and ethyl acetate (75mL) were added and the two phases were separated further the aqueous phase was extracted with ethyl acetate (2 × 25 mL), the combined organic extracts were dried over sodium sulfate, filtered, and the solvent was evaporated the crude residue was purified by silica gel chromatography (0% to 15% methanol/dichloromethane gradient over 30min) to give the desired 3- [3- [1- (trifluoromethyl) cyclopropyl ] as an off-white solid ]Propoxy group]Pyrrolidin-2-one (555mg, 83%).¹H NMR (400MHz, chloroform-d) 6.65 (width s, 1H), 3.95(dd, J ═ 7.7, 7.0Hz, 1H), 3.84(dt, J ═ 9.2, 6.2Hz, 1H), 3.54(dt, J ═ 9.2, 6.3Hz, 1H), 3.41(dddd, J ═ 9.7, 8.5, 3.7, 1.1Hz, 1H), 3.33-3.23(m, 1H), 2.40(d, J ═ 13.1, 7.6, 3.7Hz, 1H), 2.09-1.96 (m, 1H), 1.80-1.69(m, 2H), 1.69-1.52(m, 2H), 0.98-0.85(m, 2H), 0.64-0.47(m, 2H). ESI-MS M/z calculated 251.11331, Experimental 252.1(M +1)⁺(ii) a Retention time: 1.32min (LC method B).

Step 2: (14S) -12, 12-dimethyl-8- (2-oxo-3- {3- [1- (trifluoromethyl)Yl) cyclopropyl]Propoxy pyrrolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 242) and (14S) -12, 12-dimethyl-8- (2-oxo-3- {3- [1- (trifluoromethyl) cyclopropyl]Propoxy pyrrolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 243)

A4 mL vial was charged with (14S) -8-chloro-12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (32mg, 0.07112 mmol), 3- [3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrrolidin-2-one (25mg, 0.09950mmol), Pd₂(dba)₃(11mg, 0.01201mmol), xanthphos (11mg, 0.01901mmol), cesium carbonate (110 mg, 0.3376mmol) and anhydrous dioxane (0.6 mL). The mixture was sparged with nitrogen for about 3min, capped and stirred at 120 ℃ for 16h the organic solvent was concentrated by blowing nitrogen into the vial, the reaction was diluted with dimethyl sulfoxide (900 μ L), microfiltered and subjected to reverse phase preparative HPLC (C) using a gradient of acetonitrile in water (30% to 99% over 15min) and hydrochloric acid as a modifier (ca)₁₈). The pure fractions were collected and the organic solvent was evaporated the resulting aqueous solution was extracted with ethyl acetate (3 ×) and the combined organic phases were dried over sodium sulfate filtered and the solvent evaporated to give a solid which was purified by flash chromatography on silica gel using a gradient of methanol in dichloromethane (0% to 5% over 30 min). The pure fractions were combined and the solvent evaporated the residue was triturated with dichloromethane/hexane and the solvent evaporated, yielding a mixture of diastereomers which was passed over chiral SFC (ChiralCel OJ-H (250X 10mM), 5. mu.M column; mobile phase: 24% acetonitrile/methanol (90: 10; 20 mM NH) ₃)，76% carbon dioxide, 10 mL/min; concentration: 23 mg/mL: in acetonitrile/methanol (90: 10; 20mM NH)₃) Performing the following steps; injection volume 70 μ L, 100 bar). The first diastereomer to elute was (14S) -12, 12-dimethyl-8- (2-oxo-3- {3- [1- (trifluoromethyl) cyclopropyl]Propoxy pyrrolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 242) (6.3mg, 26%). ESI-MS M/z calculated 664.2655, Experimental 665.4(M +1)⁺(ii) a Retention time: 2.05min (LC method B). The second diastereomer to elute was (14S) -12, 12-dimethyl-8- (2-oxo-3- {3- [1- (trifluoromethyl) cyclopropyl]Propoxy pyrrolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 243) (5.2mg, 22%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.45 (width s, 1H), 7.70(d, J ═ 8.4Hz, 1H), 7.61-7.47(m, 2H), 7.04(d, J ═ 7.2Hz, 1H), 6.96(s, 1H), 6.69(d, J ═ 8.5Hz, 1H), 4.30(t, J ═ 8.4Hz, 1H), 3.92(t, J ═ 9.8Hz, 2H), 3.82-3.70 (m, 2H), 3.60-3.49(m, 1H), 3.10(br s, 1H), 2.93(d, J ═ 13.3Hz, 1H), 2.74-2.64 (m, 1H), 2.48-2.36(m, 1H), 2.10(br s, 1H), 1H, 1.68(m, 1H), 3.68 (m, 3.68, 1H), 0.3.83-2H, 3.3.3 (m, 1H), 2.3.70 (m, 2H). ESI-MS M/z calculated 664.2655, Experimental 665.4(M +1) ⁺(ii) a Retention time: 2.06min (LC method B).

Example 74: preparation of (14S) -8- {3- [ (adamantan-1-yl) methoxy]-2-oxopyrrolidin-1-yl } -12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 244) and (14S) -8- {3- [ (adamantan-1-yl) methoxy]-2-oxopyrrolidin-1-yl } -12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (Compound 245)

Step 1: 3- (1-adamantylmethoxy) pyrrolidin-2-one

To a solution of 1-adamantanemethanol (0.500g, 3.007mmol) and 3-bromopyrrolidin-2-one (0.493g, 3.007mmol) in anhydrous tetrahydrofuran (20mL) was added a solution of 1M potassium bis (trimethylsilyl) amide in tetrahydrofuran (6.3mL, 6.30mmol) at-60 ℃. The reaction was stirred at this temperature for 20min, then raised to 0 ℃ and stirred for an additional 2h the reaction was quenched with saturated aqueous ammonium chloride solution (20mL) and extracted with ethyl acetate (3 × 20 mL.) the combined organic layers were washed with brine (20mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was triturated with hexanes (30mL) and the solid formed was collected by filtration to give 3- (adamantan-1-ylmethoxy) -pyrrolidin-2-one (0.594g, 79%) as a white solid. ¹H-NMR (250 MHz, dimethylsulfoxide-d)₆) d (ppm): 7.77(s, br, 1H), 3.82(t, J ═ 7.3Hz, 1H), 3.31(M, 1H), 3.11(M, 2H), 3.30(d, J ═ 9Hz, 1H), 2.26(M, 1H), 1.92-1.48(M, 16H), ESI-MS M/z calculated 249.17, experimental 250.2(M +1)⁺(ii) a Retention time: 4.97min (LC method Q).

Step 2: (14S) -8- {3- [ (adamantan-1-yl) methoxy]-2-oxopyrrolidin-1-yl } -12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer pair 1) (compound 244) and (14S) -8- {3- [ (adamantan-1-yl) methoxy]-2-oxopyrrolidin-1-yl } -12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (22), 5, 7, 9, 19(23), 20-hexaen-2,2, 4-trione (diastereomer pair 2) (Compound 245)

A4 mL vial was charged with (14S) -8-chloro-12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (35mg, 0.07779 mmol), 3- (1-adamantylmethoxy) pyrrolidin-2-one (30mg, 0.1203mmol), Pd ₂(dba)₃(10 mg, 0.01092mmol), xanthphos (12mg, 0.02074mmol), cesium carbonate (130mg, 0.3990 mmol) and anhydrous dioxane (0.6 mL.) the mixture was sparged with nitrogen for about 3min, capped and stirred at 120 ℃ for 22 h. The organic solvent was concentrated by blowing nitrogen into the vial. The reaction was diluted with dimethyl sulfoxide (900 μ L), microfiltered and subjected to reverse phase preparative HPLC (C) using a gradient of acetonitrile in water (30 to 99% over 15min) and hydrochloric acid as modifier (950 μ L injection)₁₈) The pure fractions were collected and the organic solvent was evaporated, the solid was extracted with ethyl acetate (2 ×) and the organic phase was dried over sodium sulfate. Filtration followed by evaporation of the solvent gave a solid which was purified by flash chromatography on silica gel using a gradient of methanol in dichloromethane (0% to 5% over 30 min.) the pure fractions were collected and the solvent was evaporated the residue was triturated with dichloromethane/hexane and the solvent was evaporated to give a mixture of diastereomers which was passed through a chiral SFC ((ChiralCel OJ-H (250X 10mM), 5. mu.M column; mobile phase: 31% acetonitrile/methanol (90: 10, 20mM NH. sub.H.))₃) 69% carbon dioxide, 10 mL/min; at a concentration of 23mg/mL in acetonitrile: methanol (90: 10; 20mM NH 3); injection volume 70. mu.L, 100 bar) the first diastereomer to be eluted was (14S) -8- {3- [ (adamantan-1-yl) methoxy ]-2-oxopyrrolidin-1-yl } -12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 244) (6.3mg, 23%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.46 (width s, 1H), 7.70(d, J ═ 8.4Hz, 1H), 7.56(t, J ═ 7.9Hz, 1H), 7.50(d, J ═ 8.4Hz, 1H), 7.03(d, J ═ 7.2Hz, 1H), 6.95(br s, 1H), 6.69(d, J ═ 8.4Hz, 1H), 4.19(t, J ═ 8.1Hz, 1H), 4.02(t, J ═ 9.3Hz, 1H), 3.98-3.84(m, 1H), 3.69(dt, J ═ 10.4, 7.5Hz, 1H), 3.41 (d, J ═ 9.0Hz, 2H), 3.11(d, J ═ 9.0, 2H), 2.93 (J ═ 2H), 2.93 (H, 2H), 1H), 1H, 11(d, 19 (H, J ═ 2H, 1H), 1H, 11 (m, 11 (H, 11) and m, 11 (H), 2H, 11 (H, 11, 1H), 2H, 1, experimental value 663.5(M +1)⁺(ii) a Retention time: 2.41min (LC method B). The second diastereomer to be eluted was (14S) -8- {3- [ (adamantan-1-yl) methoxy]-2-oxopyrrolidin-1-yl } -12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 245) (5.6mg, 20%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.45 (width s, 1H), 7.70(d, J ═ 8.4Hz, 1H), 7.61-7.48(m, 2H), 7.04(d, J ═ 7.2Hz, 1H), 6.95(br s, 1H), 6.69(d, J ═ 8.5Hz, 1H), 4.24(t, J ═ 8.3Hz, 1H), 3.92(t, J ═ 9.5Hz, 2H), 3.77 (q, J ═ 9.4, 8.8Hz, 1H), 3.41(d, J ═ 8.9Hz, 2H), 3.10(d, J ═ 9.0Hz, 2H), 2.93(d, J ═ 13.3Hz, 1H), 2.77-2.64(m, 1H), 2.46-2.46 (d, 1.4 Hz, 1H), 1H, 10(d, 38, 72, 1H), 1H, and 1H.

ESI-MS M/z calculated 662.325, Experimental 663.5(M +1)⁺(ii) a Retention time: 2.41min (LC method B).

Example 75: preparation of (14S) -8- {3- [ (4, 4-dimethylpentyl) oxy]-2-oxopyrrolidin-1-yl } -12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 246) and (14S) -8- {3- [ (4, 4-dimethylpentyl) oxy]-2-oxopyrrolidin-1-yl } -12, 12-dimethyl-2. lambda ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 247)

Step 1: 3- (4, 4-dimethylpentyloxy) pyrrolidin-2-one

A100 mL flask was charged with 4, 4-dimethylpentan-1-ol (0.97g, 8.348mmol), 3-bromopyrrolidin-2-one (1.41g, 8.598mmol), and anhydrous tetrahydrofuran (5mL) under nitrogen. The mixture was cooled in an ice-water bath and KHMDS solution (17mL, 1M, 17.00mmol) was added over 10min (the solution quickly turned brown). After stirring the mixture in a cooling bath to warm to room temperature overnight.24 h, the reaction was cooled in an ice-water bath and treated with acetic acid (1mL, 17.58mmol) and brine (50 mL.) the product was extracted with ethyl acetate (2 × 40 mL.) the combined organic extracts were washed with sodium sulfate, filtered and the solvent evaporated to give the crude material (430mg). silica gel flash chromatography of the residue using a gradient of methanol in dichloromethane (0% to 15% over 20min) gave 3- (4, 4-dimethylpentyloxy) pyrrolidin-2-one as a brown solid (239mg, 14%).¹H NMR (400MHz, chloroform-d) 5.85 (width s, 1H), 3.97(dd, J ═ 7.7, 6.9Hz, 1H), 3.83(ddd, J ═ 8.9, 7.4, 6.6Hz, 1H), 3.52(dt, J ═ 9.0, 7.1Hz, 1H), 3.43(dddd, J ═ 9.6, 8.4, 3.8, 1.2Hz, 1H), 3.29(dd, J ═ 9.6, 7.5, 6.7, 0.8Hz, 1H), 2.42(dtd, J ═ 13.1, 7.6, 3.9Hz, 1H), 2.09(ddt, J ═ 13.0, 8.4, 6.8, 1H), 1.68-1.49(M, 2.8H), 11.84 (MS, 21H), 11.8, 1H), 11.8, 11H, 11M ═ 13.8, 11H, 11M (M + M), M + 2H), M + M (M, M + M, M + M (calculated values) ⁺(ii) a Retention time: 1.3min (LC method B).

Step 2: 2-chloro-6- [3- (4, 4-dimethylpentyloxy) -2-oxo-pyrrolidin-1-yl ] pyridine-3-carboxylic acid ethyl ester

A100 mL flask was charged with ethyl 2, 6-dichloropyridine-3-carboxylate (336mg, 1.527 mmol) and 3- (4, 4-dimethylpentyloxy) pyrrolidin-2-one (287mg, 1.440mmol) in dry N, N-dimethylformamide (6mL) under nitrogen, potassium carbonate (271mg, 1.961mmol) (325 mesh) was added, followed by 1, 4-diazabicyclo [2.2.2 ] 1]Octane (25mg, 0.2229 mmol). The mixture was stirred at ambient temperature under nitrogen. After 2 days, the reaction was quenched by addition of water (50mL) followed by extraction with ethyl acetate (2X 25 mL). The organic phase was dried over sodium sulfate, filtered, and the solvent was evaporated. The product was purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexane (0% to 50% over 20 min). The pure fractions were collected and the solvent was evaporated to give 2-chloro-6- [3- (4, 4-dimethylpentyloxy) -2-oxo-pyrrolidin-1-yl as a slowly solidifying colorless resin]Pyridine-3-carboxylic acid ethyl ester (358mg, 65%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)8.36(d, J ═ 8.6Hz, 1H), 8.32(d, J ═ 8.6Hz, 1H), 4.38-4.26(m, 3H), 4.02(ddd, J ═ 11.1, 8.9, 2.6Hz, 1H), 3.81-3.67(m, 2H), 3.54(dt, J ═ 9.3, 6.6Hz, 1H), 2.49-2.39(m, 1H), 1.92(dq, J ═ 12.4, 8.8Hz, 1H), 1.58-1.44(m, 2H), 1.32(t, J ═ 7.1Hz, 3H), 1.25-1.16(m, 2H), 0.87(s, 9H). ESI-MS M/z calculated 382.16592, Experimental 383.3(M +1) ⁺(ii) a Retention time: 2.26min (LC method B).

And step 3: 6- [ [ 3-carboxy-3- (4, 4-dimethylpentyloxy) propyl ] amino ] -2-chloro-pyridine-3-carboxylic acid

In a 100mL flask, 2-chloro-6- [3- (4, 4-dimethylpentyloxy) -2-oxo-pyrrolidin-1-yl group was stirred]Pyridine-3-carboxylic acid ethyl ester (335mg, 0.8749mmol) in methanol (5mL) and tetrahydrofuran (5mL) until homogeneous sodium hydroxide (1mL, 2M, 2.000mmol) (2M aq.) is added to the mixture and the mixture is stirredThe cloudy mixture was stirred at ambient temperature for 9h sodium hydroxide (1mL, 6N) was added again and the mixture was stirred overnight. The reaction was diluted with water (40 mL.) the solution was acidified by slow addition of 6N hydrochloric acid until pH 2 the solid was extracted with ethyl acetate (2 x 50mL, 1 x 25mL) and the combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo the residue triturated with dichloromethane/hexane and the solvent evaporated to give 6- [ [ 3-carboxy-3- (4, 4-dimethylpentyloxy) propyl ] as an off-white solid]Amino group]-2-chloro-pyridine-3-carboxylic acid (333mg, quantitative yield).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.60(s, 2H), 7.87(d, J ═ 8.6Hz, 1H), 7.61(t, J ═ 5.6Hz, 1H), 6.44(d, J ═ 8.7Hz, 1H), 3.83(dd, J ═ 8.9, 3.8 Hz, 1H), 3.50(dt, J ═ 8.9, 6.6Hz, 1H), 3.42-3.36(m, 1H), 3.34 (width s, partially overlapping with the water signal, 1H), 3.25(dt, J ═ 8.9, 6.7Hz, 1H), 2.00-1.85(m, 1H), 1.85-1.73(m, 1H), 1.52-1.39(m, 2H), 1.20-1.12(m, 2H), 0.84(s, 9H). ESI-MS M/z calculated 372.1452, Experimental 373.2(M +1) ⁺(ii) a Retention time: 1.47min (LC method B).

And 4, step 4: 2-chloro-6- [3- (4, 4-dimethylpentyloxy) -2-oxo-pyrrolidin-1-yl ] pyridine-3-carboxylic acid

A100 mL flask was charged with 6- [ [ 3-carboxy-3- (4, 4-dimethylpentyloxy) propyl ] under nitrogen]Amino group]-2-chloro-pyridine-3-carboxylic acid (281mg, 0.7537mmol), HATU (292mg, 0.7680mmol) and anhydrous tetrahydrofuran (6mL) (topical suspension). Triethylamine (0.34mL, 2.439mmol) was added (quick to yellow homogeneous solution) and the mixture was stirred at room temperature for 2 days water (30mL) was added, followed by hydrochloric acid (200 μ L, 6M, 1.200mmol) (6N aqueous solution, final pH 4.) the resulting white solid was filtered and washed with water to give pure 2-chloro-6- [3- (4, 4-dimethylpentyloxy) -2-oxo-pyrrolidin-1-yl as a white solid]Pyridine-3-carboxylic acid (196mg, 73%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)13.51(s，1H)，8.34(d， J＝8.6Hz，1H)，8.31(d，J＝8.6Hz，1H) 4.33(dd, J ═ 8.9, 7.9Hz, 1H), 4.01(ddd, J ═ 11.2, 8.8, 2.6Hz, 1H), 3.82-3.67(M, 2H), 3.54(dt, J ═ 9.2, 6.6Hz, 1H), 2.48-2.37 (M, 1H), 1.91(dq, J ═ 12.4, 8.9Hz, 1H), 1.58-1.44(M, 2H), 1.27-1.14(M, 2H), 0.87(s, 9H), ESI-MS M/z 354.13464, experimental 355.3(M +1)⁺(ii) a Retention time: 1.91min (LC method B).

And 5: (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (4, 4-dimethylpentyloxy) -2-oxo-pyrrolidin-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

A100 mL round bottom flask was charged with 2-chloro-6- [3- (4, 4-dimethylpentyloxy) -2-oxo-pyrrolidin-1-yl under nitrogen]Pyridine-3-carboxylic acid (182mg, 0.5129mmol) and anhydrous tetrahydrofuran (3 mL). Carbonyldiimidazole (102mg, 0.6291mmol) was added (newly recrystallized from tetrahydrofuran) and the mixture was stirred at room temperature under nitrogen for 3h, 35mg more carbonyldiimidazole was added and the mixture was stirred at room temperature for 2 h. Preparation of (4S) -2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino group in a separate 20mL flask under a nitrogen atmosphere]Propyl radical]A solution of pyrrolidine-1-carboxylic acid tert-butyl ester (211mg, 0.5115mmol) in anhydrous tetrahydrofuran (1.5mL) and was then added to the activated ester solution by syringe. Addition of 1, 8-diazabicyclo [5.4.0 ] via syringe]Undec-7-ene (0.38mL, 2.541mmol) and the reaction mixture was stirred at room temperature under a nitrogen atmosphere overnight. After 2 days, the solvent was removed under reduced pressure and the resulting thick oil was treated with ethyl acetate (20mL) and water (20 mL). Hydrochloric acid (600 μ L, 6M, 3.600mmol) was added slowly (final pH 5) and the two phases were separated. The aqueous phase was extracted with ethyl acetate (30 mL). The combined extracts were washed with brine (30mL) and dried over sodium sulfate. After evaporation of the solvent, the residue was dissolved in dichloromethane and purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexane (0% to 100% over 30min) to give (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (4, 4-dimethylpentyloxy) -2-oxo-pyrrolidin-1-yl ] methyl ester]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (138mg, 36%, 90% purity). ESI-MS M/z calculated 748.3385, Experimental 749.5(M +1)⁺(ii) a Retention time: 2.42min (LC method B).

Step 6: 2-chloro-6- [3- (4, 4-dimethylpentyloxy) -2-oxo-pyrrolidin-1-yl ] -N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] propylamino ] -2-pyridyl ] sulfonyl ] pyridine-3-carboxamide (dihydrochloride)

A100 mL flask was charged with (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (4, 4-dimethylpentyloxy) -2-oxo-pyrrolidin-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (138mg, 0.1842mmol), dichloromethane (2mL) and hydrochloric acid (300 μ L, 4M in dioxane, 1.200 mmol.) the reaction was stirred at room temperature for 3.5h (60% conversion.) the other amount of hydrochloric acid (300 μ L, 4M, 1.200mmol) was added and the reaction was stirred for an additional 2 h. The volatiles were removed by evaporation in vacuo the residue was triturated with dichloromethane/hexanes and the solvent was evaporated. This procedure was repeated until a white solid was obtained vacuum drying to give 2-chloro-6- [3- (4, 4-dimethylpentyloxy) -2-oxo-pyrrolidin-1-yl as a white solid ]-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] radical]Propylamino group]-2-pyridyl]Sulfonyl radical]Pyridine-3-carboxamide (dihydrochloride) (125mg, 94%). the product was used in the next step without any further purification. ESI-MS M/z calculated 648.2861, Experimental 649.4(M +1)⁺(ii) a Retention time: 1.62min (LC method B).

And 7: (14S) -8- {3- [ (4, 4-dimethylpentyl) oxy]-2-oxopyrrolidin-1-yl } -12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer pair 1) (compound 246) and (14S) -8- {3-[ (4, 4-dimethylpentyl) oxy]-2-oxopyrrolidin-1-yl } -12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer pair 2) (compound 247)

A50 mL round-bottomed flask equipped with a magnetic stir bar was charged under nitrogen with 2-chloro-6- [3- (4, 4-dimethylpentyloxy) -2-oxo-pyrrolidin-1-yl]-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] radical]Propylamino group]-2-pyridyl ]Sulfonyl radical]Pyridine-3-carboxamide (dihydrochloride) (125mg, 0.1731), anhydrous NMP (7 mL) and potassium carbonate (465mg, 3.365mmol) (325 mesh.) the mixture was stirred vigorously in a dry bath at 155 ℃ for 20h under nitrogen. After cooling to room temperature, the mixture was poured into cooling water (50mL) and acidified (slightly foaming) by addition of hydrochloric acid (1mL, 6M, 6.000mmol), the resulting solid was filtered and approximately air dried, the solid was dissolved in dichloromethane and purified by silica gel flash chromatography using a gradient of methanol in dichloromethane (0% to 5% over 30min) to give a mixture of diastereomers, which was subjected to chiral SFC separation (ChiralCel OJ-H (250X 10mM), 5. mu.M column, mobile phase 24% acetonitrile/methanol (90: 10; 20mM NH)₃) 76% carbon dioxide, 10 mL/min; at a concentration of 23mg/mL in acetonitrile/methanol (90: 10; 20mM NH)₃) Performing the following steps; injection volume 70 μ L, 100 bar) to give (14S) -8- {3- [ (4, 4-dimethylpentyl) oxy as the first diastereomer to elute]-2-oxopyrrolidin-1-yl } -12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 246) (22mg, 20%). ¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.43(s, 1H), 7.70(d, J ═ 8.4Hz, 1H), 7.56(t, J ═ 7.8Hz, 1H), 7.51(d, J ═ 8.3Hz, 1H), 7.04(d, J ═ 7.2Hz, 1H), 6.96 (width s, 1H), 6.70(d, J ═ 8.5Hz, 1H), and so on1H), 4.24(t, J ═ 8.2Hz, 1H), 4.03(t, J ═ 8.7Hz, 1H), 3.95-3.87(br m, 1H), 3.81-3.64(m, 2H), 3.52(dt, J ═ 9.2, 6.6Hz, 1H), 3.12(br s, 1H), 2.94(d, J ═ 13.5Hz, 1H), 2.78-2.61(m, 1H), 2.42(dq, J ═ 13.0, 7.9, 6.3Hz, 1H), 2.11 (width s, 1H), 1.92(dq, J ═ 12.3, 8.6Hz, 1H), 1.85-1.68(m, 2H), 1.64-1.41 (m, 10H), 1.36.36 (m, 1H), 4.87 (m, 0H), 13.9 (m, 1H). ESI-MS M/z calculated 612.3094, Experimental 613.4(M +1)⁺(ii) a Retention time: 2.17min (LC method B.) the second diastereomer to be eluted was (14S) -8- {3- [ (4, 4-dimethylpentyl) oxy]-2-oxopyrrolidin-1-yl } -12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 247) (21mg, 19%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.41(s, 1H), 7.70(d, J ═ 8.4Hz, 1H), 7.59-7.51(m, 2H), 7.04(d, J ═ 7.2Hz, 1H), 6.96 (width s, 1H), 6.70(d, J ═ 8.5Hz, 1H), 4.28(t, J ═ 8.4Hz, 1H), 3.92(t, J ═ 9.8Hz, 2H), 3.83-3.68(m, 2H), 3.52(dt, J ═ 9.2, 6.6Hz, 1H), 3.10(br s, 1H), 2.94(br d, J ═ 13.4Hz, 1H), 2.80-2.59(m, 1H), 2.48-2.37(m, 1H), 2.10(br s, 1H), 1.68 (br d, J ═ 13.4Hz, 1H), 2.80-2.59(m, 1H), 2.48-2.37(m, 1H), 1H. ESI-MS M/z calculated 612.3094, Experimental 613.4(M +1) ⁺(ii) a Retention time: 2.17min (LC method B).

Example 76: preparation of 12, 12-dimethyl-8- {3- [ 3-methyl-2- (prop-2-yl) butoxy]-1H-pyrazol-1-yl } -15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 248) and 12, 12-dimethyl-8- {3- [ 3-methyl-2- (prop-2-yl) butoxy]-1H-pyrazol-1-yl } -15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 249)

Step 1: 12, 12-dimethyl-8- {3- [ 3-methyl-2- (prop-2-yl) butoxy]-1H-pyrazol-1-yl } -15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 248) and 12, 12-dimethyl-8- {3- [ 3-methyl-2- (prop-2-yl) butoxy]-1H-pyrazol-1-yl } -15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 249)

To racemic 12, 12-dimethyl-8- {3- [ 3-methyl-2- (prop-2-yl) butoxy]-1H-pyrazol-1-yl } -15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (60mg, 0.09612mmol) was subjected to chiral SFC chromatography using the following SFC protocol: ChiralPak AS-3 (150X 2.1mm), 3 μm; 35 ℃ mobile phase: 30% acetonitrile: methanol (90: 10), 70% carbon dioxide the first enantiomer to be eluted was 12, 12-dimethyl-8- {3- [ 3-methyl-2- (propan-2-yl) butoxy]-1H-pyrazol-1-yl } -15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 248) (21mg, 71%). ESI-MS M/z calculated 611.289, Experimental 612.2 (M +1)⁺(ii) a Retention time: 2.30min (LC method B) the second enantiomer to be eluted was 12, 12-dimethyl-8- {3- [ 3-methyl-2- (prop-2-yl) butoxy]-1H-pyrazol-1-yl } -15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5(10), 6, 8, 19, 21-hexaene-2, 2, 4-trione (enantiomer 2) (compound 249) (22mg, 74%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.56(s, 1H), 8.19(d, J ═ 2.8Hz, 1H), 7.78(d, J ═ 8.2Hz, 1H), 7.59(dd, J ═ 8.5, 7.2Hz, 1H), 7.10(t, J ═ 7.4Hz, 2H), 6.95(d, J ═ 8.2Hz, 1H), 6.70(d, J ═ 8.5 Hz, 1H), 6.11(d, J ═ 2.7Hz, 1H), 4.23(d, J ═ 4.8Hz, 2H), 4.11(t, J ═ 8.3Hz, 2H), 3.88(t, J ═ 12.0Hz, 1H), 3.60(d, J ═ 12.9, 1H), 3.23(s, 3.3, 1H), 1H (s, 1.9, 2H), 1H, 7.7H, 1H, 7H, 1H, 7H, 1H, 7H, 1H, 7H, 1H, 7H, and 7H, j6.8 Hz, 6H), 0.92(d, J6.8 Hz, 6H), ESI-MS calculated M/z 611.289, experimental 612.2(M +1)⁺(ii) a Retention time: 2.29min (LC method B).

Example 77: preparation of 11- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl]-7, 7-dimethyl-17. lambda.⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosane-1 (22), 9, 11, 13, 18, 20-hexaene-15, 17, 17-trione (enantiomer 1) (compound 251)

Step 1: 2, 2-dimethyl-4- [2- [ (6-sulfamoyl-2-pyridyl) amino ] ethyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

Racemic 2, 2-dimethyl-4- [2- (6-sulfamoyl-2-pyridyl) amino group was purified by chiral SFC using ChiralPak IG (250X 21.2mm column, 5 μm particle size) and 32% methanol (no modifier))/68% carbon dioxide mobile phase (70mL/min)]Ethyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (1.475g, 3.701mmol) was isolated to give 2, 2-dimethyl-4- [2- (6-sulfamoyl-2-pyridyl) amino as the first enantiomer to be eluted as a white foam]Ethyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (enantiomer 1) (670mg, 91%). ESI-MS M/z calculated 398.19876, Experimental 399.3(M +1)⁺(ii) a Retention time: 1.59min (LC method B).

Step 2: 4- [2- [ [6- [ [ 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] ethyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (enantiomer 1)

To the flask was added 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (147.7 mg, 0.4082mmol), recrystallized carbonyldiimidazole (66.2mg, 0.4083mmol) and tetrahydrofuran (4 mL). The reaction was stirred at 40 ℃ for 90min, then 2, 2-dimethyl-4- [2- [ (6-sulfamoyl-2-pyridyl) amino group was added ]Ethyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (enantiomer 1) (130mg, 0.3262mmol) followed by addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (150 μ L, 1.003 mmol.) the reaction was stirred for 2 days the reaction was filtered and purified by HPLC (30% to 99% acetonitrile: water gradient + 0.1% hydrochloric acid modifier) to provide 4- [2- [ [6- [ [ 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Ethyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (enantiomer 1) (30.4mg, 13%). ESI-MS M/z calculated 741.30756, experimental value 742.4(M +1)⁺(ii) a Retention time: 2.2min (LC method G).

And step 3: 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl ] -N- [ [6- [2- (5, 5-dimethylpyrrolidin-3-yl) ethylamino ] -2-pyridinyl ] sulfonyl ] pyridine-3-carboxamide (enantiomer 1)

To a compound containing 4- [2- [ [6- [ [ 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Ethyl radical]-2，2-To a flask of tert-butyl dimethyl-pyrrolidine-1-carboxylate (enantiomer 1) (30.4mg, 0.04095mmol) were added dichloromethane (3mL) and trifluoroacetic acid (125 μ L, 1.622 mmol). The reaction was stirred at room temperature for 30 min. The reaction was evaporated to dryness and washed with a saturated aqueous solution of sodium bicarbonate. The reaction mixture was extracted with ethyl acetate, dried over sodium sulfate, filtered and evaporated to give 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl ]-N- [ [6- [2- (5, 5-dimethylpyrrolidin-3-yl) ethylamino ] amino]-2-pyridyl]Sulfonyl radical]Pyridine-3-carboxamide (enantiomer 1) (24mg, 91%). ESI-MS M/z calculated 641.2551, Experimental 642.3(M +1)⁺(ii) a Retention time: 1.76min (LC method B).

And 4, step 4: 11- [3- (3, 3-Dicyclopropylpropoxy) -1H-pyrazol-1-yl]-7, 7-dimethyl-17. lambda.⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosane-1 (22), 9, 11, 13, 18, 20-hexaene-15, 17, 17-trione (enantiomer 1) (compound 251)

To a vial were added potassium carbonate (35mg, 0.2532mmol), cesium fluoride (12mg, 0.07900mmol),

Molecular sieves and 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl]-N- [ [6- [2- (5, 5-dimethylpyrrolidin-3-yl) ethylamino ] amino]-2-pyridyl]Sulfonyl radical]Pyridine-3-carboxamide (enantiomer 1) (24mg, 0.03737mmol) in dimethylsulfoxide (1.5mL) the reaction was placed in a 150 ℃ oil bath and stirred overnight. The reaction was cooled to room temperature, filtered and purified by HPLC (10% -99% acetonitrile: water gradient + 0.1% hydrochloric acid modifier) to give 11- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl ]-7, 7-dimethyl-17. lambda.⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosane-1 (22), 9, 11, 13, 18, 20-hexaene-15, 17, 17-trione (enantiomer 1) (compound 251) (9.3mg, 41％)。¹h NMR (400MHz, dimethylsulfoxide-d)₆)12.45(s, 1H), 8.20(d, J ═ 2.8Hz, 1H), 7.74(d, J ═ 33.0Hz, 2H), 7.17(s, 1H), 6.90(d, J ═ 8.2Hz, 1H), 6.82(s, 1H), 6.10(d, J ═ 2.8Hz, 1H), 4.37(t, J ═ 6.8Hz, 2H), 2.25(s, 3H), 1.90(q, J ═ 6.8Hz, 4H), 1.56(s, 6H), 1.49(s, 2H), 0.68(dtd, J ═ 13.4, 8.6, 5.0Hz, 2H), 0.46 to 0.34(m, 5H), 0.30(d, J ═ 15.8, 8, 7.9, 0.09H), 0.15.02 to 0.5H), 0.15.9 (m, 2H). Both protons are masked by the solvent. ESI-MS M/z calculated 605.27844, Experimental 606.2(M +1)⁺(ii) a Retention time: 2.3min (LC method B).

Example 78: preparation of (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } -2, 2-dideuterio-ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 252)

Step 1: dideuterium (dispiro [2.0.2.1] hept-7-yl) methanol

Cooling of dispiros [2.0.2.1] in an ice-water bath]A solution of heptane-7-carboxylic acid ethyl ester (2.8g, 16.84mmol) in tetrahydrofuran (35 mL). Lithium aluminum deuteride (678mg, 16.14mmol) was added in small portions over 3min and the reaction mixture was stirred at ambient temperature under nitrogen atmosphere for 5 h. The reaction was cooled with an ice-water bath and the reaction mixture was diluted with ether (40mL) and slowly quenched by addition of saturated aqueous rochelle salt solution (about 30mL) until the layers separated significantly. The aqueous layer was extracted with diethyl ether (2X 30mL) the combined organic layers were washed with brine (30mL), dried over magnesium sulfate, filtered and concentrated to give dideutero (dispiro [2.0.2.1 ]) as a pale yellow oil]Hept-7-yl) methanol (2.5g, 98%).¹H NMR (400MHz, chloroform-d) 4.82(bs, 1H), 1.62(s, 1H), 0.87(m, 4H), 0.65-0.48(m, 4H).

Step 2: 7- [ bromo (didehydro) methyl ] dispiro [2.0.2.1] heptane

To a solution of triphenylphosphine (5.3g, 20.1mmol) in dichloromethane (74 mL) at-15 deg.C under nitrogen was added a solution of bromine (1.1mL, 21.3mmol) in dichloromethane (9mL) over 15 min. The reaction mixture was stirred at-15 ℃ for a further 15min and subsequently cooled to-30 ℃. Dideuterium (dispiro [2.0.2.1 ]) was added dropwise ]Hept-7-yl) methanol (2.5g, 16.6mmol) and pyridine (1.65mL, 20.5mmol) in dichloromethane (18mL) the mixture was warmed to-5 ℃ and stirred for 1h and poured into pentane (1L). The precipitate formed is filtered off and the filtrate is concentrated pentane (300mL) is added to the residue and the mixture is sonicated and filtered the filtrate is concentrated to give a white solid which is treated again with pentane (300mL) and filtered the filtrate is concentrated and the residue is purified by chromatography on silica gel using a 0% to 5% diethyl ether/pentane gradient the fractions containing the product are combined and concentrated at 300mbar using a 30 ℃ water bath to give 7- [ bromo (didehydro) methyl ] as a white solid]Dispiro [2.0.2.1]]Heptane (2g, 58%).¹H NMR (250MHz, chloroform-d) 1.88(s, 1H), 0.8-1.0(m, 4H), 0.63-0.72(m, 2H), 0.48-0.6(m, 2H).

And step 3: 2, 2-dideuterio-2-dispiro [2.0.2.1] hept-7-yl-acetonitrile

To 7- [ bromo (didehydro) methyl]Dispiro [2.0.2.1]]To a solution of heptane (2.3g, 22.02mmol) in dimethyl sulfoxide (30mL) was added sodium cyanide (753mg, 27.53mmol) and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with brine (40mL) and extracted with pentane (2X 50 mL). The combined pentane layers were dried over magnesium sulfate, filtered and concentrated to give To 2, 2-dideuterio-2-dispiro [2.0.2.1] as a colorless oil]Hept-7-yl-acetonitrile (1.8 g, 77%).¹H NMR (250MHz, chloroform-d) 1.68(s, 1H), 0.8-1.05(m, 4H), 0.65-0.8(m, 2H), 0.54-0.62(m, 2H).

And 4, step 4: 2, 2-dideuterio-2-dispiro [2.0.2.1] hept-7-yl-acetic acid

Reacting 2, 2-dideuterio-2-dispiro [2.0.2.1] at room temperature]Hept-7-yl-acetonitrile (7.7g, 56.951mmol) was dissolved in CH₃Cwater (105mL). Sodium deuteroxide (52.2g, 40% w/w, 509.23mmol) was added followed by CH₃Cwater D (105 mL.) the mixture was heated at 72 ℃ in an oil bath under nitrogen atmosphere (balloon) for 16h, the mixture was cooled in an ice water bath for 15min, D was added₂O (about 20 mL). The aqueous mixture was extracted with ether (2X 50mL) the aqueous layer was retained and treated with hydrochloric acid (6N) until pH was about 2. The mixture was extracted with ether (3X 50mL) the combined ether layers were dried over anhydrous magnesium sulfate, filtered and concentrated to give 2, 2-didedeuterium-2-dispiro [2.0.2.1] as a pale yellow solid]Hept-7-yl-acetic acid (6g, 65%).¹H NMR (250MHz, chloroform-d) 1.64(s, 1H), 1.01-0.73(m, 4H), 0.67(ddd, J ═ 8.3, 4.9, 3.5Hz, 2H), 0.58-0.35 (m, 2H).

And 5: 2, 2-dideuterio-2-dispiro [2.0.2.1] hept-7-yl-ethanol

Lithium aluminum hydride (2.84g, 74.827mmol) was weighed into a round bottom flask and cooled in an ice-water bath under a nitrogen atmosphere (balloon). tetrahydrofuran (150mL) was added and the mixture was stirred at 0 ℃ for 10 min. Subsequently, 2-dideuterio-2-dispiro [2.0.2.1] was added dropwise over 20min]Hept-7-yl-acetic acid (8.1g, 52.528mmol) in tetrahydrofuran (20mL, 10mL rinse) the mixture was slowly warmed to room temperature and stirred for 15 h. Subsequently, it was cooled in an ice-water bath and slowly quenched with rochelle salt solution. Additive for foodEther (200mL) was added and the layers were separated and the aqueous layer was extracted with more ether (2 x 150 mL). The combined organics were dried over anhydrous magnesium sulfate, filtered and concentrated to give 2, 2-dideuterio-2-dispiro [2.0.2.1] as a pale yellow oil]Hept-7-yl-ethanol (7.5g, 89%).¹H NMR (250MHz, chloroform-d) 3.62(s, 2H), 1.69(s, 1H), 0.73-1.0(m, 4H), 0.60-0.75(m, 2H), 0.45-0.59(m, 2H).

Step 6: 3- (2, 2-Dideuterium-2-dispiro [2.0.2.1] hept-7-yl-ethoxy) pyrazole-1-carboxylic acid tert-butyl ester

To 5-oxo-1H-pyrazole-2-carboxylic acid tert-butyl ester (10.25g, 55.65mmol) and 2, 2-dideuterio-2-dispiro [2.0.2.1]]To a solution of hept-7-yl-ethanol (8.193g, 58.43mmol) in tetrahydrofuran (128.1mL) was added triphenylphosphine (15.33g, 58.45 mmol). Diisopropyl azodicarboxylate (11.82g, 58.45mmol) was added slowly dropwise to the mixture over 10 min. The reaction mixture was stirred at room temperature for 2 h. The tetrahydrofuran was removed under reduced pressure and the residue was purified by silica gel chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate to give 3- (2, 2-dideutero-2-dispiro [2.0.2.1] as a clear slurry ]Hept-7-yl-ethoxy) pyrazole-1-carboxylic acid tert-butyl ester (11.57g, 68%). ESI-MS M/z calculated 306.19125, experimental 307.2(M +1)⁺(ii) a Retention time: 0.8min (LC method A).

And 7: 3- (2, 2-dideutero-2-dispiro [2.0.2.1] hept-7-yl-ethoxy) -1H-pyrazole

Reacting 3- (2, 2-dideuterio-2-dispiro [2.0.2.1]]Hept-7-yl-ethoxy) pyrazole-1-carboxylic acid tert-butyl ester (11.57g, 37.76mmol) was dissolved in dichloromethane (115.7mL) and trifluoroacetic acid (43.64mL, 566.4mmol) and the reaction stirred at room temperature for 2h the solvent was evaporated and the resulting oil was partitioned between ethyl acetate and a saturated solution of sodium bicarbonateTwo times, then the organics were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give 3- (2, 2-dideuterio-2-dispiro [2.0.2.1] as an oil]Hept-7-yl-ethoxy) -1H-pyrazole (7.789g, 100%). ESI-MS M/z calculated 206.13881, experimental 207.1(M +1)⁺(ii) a Retention time: 0.59min (LC method A).

And 8: 2-chloro-6- [3- (2, 2-didehydro-2-dispiro [2.0.2.1] hept-7-yl-ethoxy) pyrazol-1-yl ] pyridine-3-carboxylic acid tert-butyl ester

2, 6-dichloropyridine-3-carboxylic acid tert-butyl ester (9.368g, 37.76mmol), 3- (2, 2-dideuterio-2-dispiro [2.0.2.1] ]Hept-7-yl-ethoxy) -1H-pyrazole (7.789g, 37.76mmol) and potassium carbonate (6.268g, 45.35 mmol) were combined in anhydrous dimethylsulfoxide (155.8 mL). Addition of 1, 4-diazabicyclo [2.2.2]Octane (848 mg, 7.560mmol) and the mixture stirred at room temperature under nitrogen for 16 h. The reaction mixture was diluted with water (300mL) and stirred for 15 min. The solid was filtered off and washed with water. The solid was dissolved in dichloromethane, dried over magnesium sulfate, filtered and concentrated to give 2-chloro-6- [3- (2, 2-dideuterio-2-dispiro [2.0.2.1] as a white solid]Hept-7-yl-ethoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (15.54g, 98%). ESI-MS M/z calculated 417.17883, Experimental 418.1(M +1)⁺(ii) a Retention time: 0.97min (LC method A).

And step 9: 2-chloro-6- [3- (2, 2-didehydro-2-dispiro [2.0.2.1] hept-7-yl-ethoxy) pyrazol-1-yl ] pyridine-3-carboxylic acid

2-chloro-6- [3- (2, 2-dideuterio-2-dispiro [2.0.2.1]]Hept-7-yl-ethoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (15.54g, 37.18mmol) was dissolved in dichloromethane (155.4mL) and trifluoroacetic acid (42.97mL, 557.7mmol) and the reaction was stirred at room temperature for 16 h. The solvent was evaporated and to the resulting solid was added ether and then reducedThe product is still in the filtrate, the filtrate is evaporated to give an off-white solid, which is dissolved in ethyl acetate and washed with 5N sodium hydroxide (2 ×), followed by 1N hydrochloric acid (1 ×), followed by drying (sodium sulfate), filtration and concentration to a white solid which is prepared by reverse phase HPLC-MS method using Luna C sold by Phenomenex ₁₈(2) Column (75 × 30 mM, 5 μm particle size) (pn: 00C-4252-U0-AX) and dual gradient run of 20% -80% mobile phase B over 15.0min (mobile phase a ═ water (5mM hydrochloric acid), mobile phase B ═ acetonitrile, flow rate 50mL/min, injection volume 950 μ L and column temperature 25 ℃) to give pure product material, which was combined with the original crystalline material to give 2-chloro-6- [3- (2, 2-dideuterio-2-dispiro [2.0.2.1] as a white solid]Hept-7-yl-ethoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (10.43g, 78%). ESI-MS M/z calculated 361.1162, Experimental 362.1(M +1)⁺(ii) a Retention time: 0.78min (LC method A).

Step 10: (4S) -4- [3- [ [6-I [ 2-chloro-6- [3- (2, 2-didehydro-2-dispiro [2.0.2.1] hept-7-yl-ethoxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To 2-chloro-6- [3- (2, 2-dideuterio-2-dispiro [2.0.2.1]]Hept-7-yl-ethoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (2g, 5.528mmol) in tetrahydrofuran (13.66mL) carbonyl diimidazole (1.12g, 6.907 mmol) was added (newly recrystallized from tetrahydrofuran) and the mixture was stirred at room temperature for 3h, then (4S) -2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino was added as a solution in tetrahydrofuran (5mL) ]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (2.383g, 5.776mmol) was added followed by 1, 8-diazabicyclo [5.4.0]Undec-7-ene (2.594mL, 17.35mmol) and the resulting mixture was stirred at room temperature for 3hAnd then hydrochloric acid (6.178mL, 6M, 37.07mmol) was added to the aqueous layer (pH 1). The layers were separated and the organic layer was washed with water (1 ×) and brine (1 ×), then dried over sodium sulfate, filtered and concentrated to a white foam which was subjected to 275g C₁₈Purifying with reverse phase column, eluting with 50% -100% acetonitrile/water gradient to obtain (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (2, 2-didehydro-2-dispiro [2.0.2.1 ]) as white solid]Hept-7-yl-ethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (3.0854g, 74%). ESI-MS M/z calculated 755.32007, Experimental 756.1(M +1)⁺(ii) a Retention time: 0.93min (LC method A).

Step 11: 2-chloro-6- [3- (2, 2-didehydro-2-dispiro [2.0.2.1] hept-7-yl-ethoxy) pyrazol-1-yl ] -N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] propylamino ] -2-pyridinyl ] sulfonyl ] pyridine-3-carboxamide

Mixing (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (2, 2-didehydro-2-dispiro [2.0.2.1] ]Hept-7-yl-ethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (3.0854g, 4.079mmol) was dissolved in dichloromethane (13.46mL) and trifluoroacetic acid (12.57 mL, 163.2mmol) was added and the mixture was stirred at room temperature for 90min. Toluene (50mL) was added and the mixture was evaporated by rotary evaporation (45 ℃ water bath). Toluene (50mL) was added again and removed by rotary evaporation (45 ℃ water bath) followed by vacuum drying to give 2-chloro-6- [3- (2, 2-dideutero-2-dispiro [2.0.2.1 ] as a white solid]Hept-7-yl-ethoxy) pyrazol-1-yl]-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] radical]Propylamino group]-2-pyridyl]Sulfonyl radical]Pyridine-3-carboxamide (trifluoroacetate) (3.142g, 100%). ESI-MS M/z calculated 655.26764, Experimental 656.2(M +1)⁺(ii) a Retention time: 0.65min (LC method A).

Step 12: (14S) -8- [3- (2- { dispiro [2.0.2 ].1]Hept-7-yl } -2, 2-dideuterio-ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 252)

To 2-chloro-6- [3- (2, 2-dideuterio-2-dispiro [2.0.2.1 ]]Hept-7-yl-ethoxy) pyrazol-1-yl]-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] radical]Propylamino group]-2-pyridyl]Sulfonyl radical]To a solution of pyridine-3-carboxamide (trifluoroacetate) (3.142g, 4.079mmol) in NMP (188.5mL) was added potassium carbonate (3.946g, 28.55mmol), the mixture was purged with nitrogen for 5min and heated at 150 ℃ for 24 h. The reaction mixture was cooled to room temperature and added to water (about 200mL) to give an off-white solid. The mixture was carefully acidified with hydrochloric acid (6.798mL, 6M, 40.79mmol) to give a multivesicular slurry. The solid was collected by filtration and the wet cake was dissolved in ethyl acetate and washed with brine (1 ×) and a small amount of 6N hydrochloric acid to maintain clarity in the layer. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give a light yellow oil which was subjected to 275g C₁₈Subjecting to reverse phase column chromatography, eluting with 50% -100% acetonitrile/water to obtain (14S) -8- [3- (2- { dispiro [2.0.2.1 ] as white solid]Hept-7-yl } -2, 2-dideuterio-ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 252) (2.16g, 85%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.50(s，1H)，8.20(d，J＝2.8Hz，1H)，7.81(d，J＝8.2 Hz，1H)，7.58(dd，J＝8.5，7.2Hz，1H)，7.05(d，J＝7.1Hz，1H)，6.98(d，J＝8.7Hz， 1H)，6.91(d，J＝8.2Hz，1H)，6.71(d，J＝8.5Hz，1H)，6.08(d，J＝2.7Hz，1H)，4.20 (d，J＝1.4Hz，2H)，3.92(d，J＝12.9Hz，1H)，3.17(d，J＝5.0Hz，1H)，2.95(d，J＝ 13.1Hz，1H)，2.69(d，J＝13.8Hz, 1H), 2.13(s, 1H), 1.86(dd, J ═ 11.6, 5.2Hz, 1H), 1.77(s, 1H), 1.59(d, J ═ 7.7Hz, 6H), 1.51(s, 3H), 1.46(s, 1H), 1.38-1.24(M, 1H), 0.83(s, 4H), 0.69-0.60(M, 2H), 0.55-0.44(M, 2H), ESI-MS M/z calculated 619.29095, experimental 620.2(M +1)⁺(ii) a Retention time: 2.37min (LC method B).

Example 79: preparation of (14S) -8- (3- {2- [ (7-deuterium) dispiro [2.0.2.1]]Hept-7-yl]Ethoxy } -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 253)

Step 1: 7-deuterium dispiro [2.0.2.1] heptane-7-carboxylic acid ethyl ester

A solution of cyclopropylene cyclopropane (5.3g, 66.1mmol) in dichloromethane (15mL) was cooled in an ice-water bath rhodium (II) acetate dimer (600mg, 5.2038mmol) was added in one portion. The mixture was stirred at 0-5 ℃ for 5min under nitrogen atmosphere. Ethyl 2-deuterium-2-diazo-acetate (20mL, 152mmol) prepared according to JACS, 1993, 115, 2239 was then added by a syringe pump at a rate of 0.11 mL/h. The mixture was stirred for a further 10min after the addition was complete the mixture was concentrated to a volume of 50mL and filtered through a pad of silica gel. The pad was washed with dichloromethane (200mL) and the combined filtrates were concentrated to a volume of 50mL, filtered again and washed with dichloromethane (300 mL). The filtrate was concentrated to give 7-deuterodispiro [2.0.2.1] as a pale yellow oil ]Heptane-7-carboxylic acid ethyl ester (9g, 66.25%).¹H NMR (250MHz, chloroform-d) 4.13(q, J ═ 7.1Hz, 2H), 1.39-1.14(m, 4H), 1.11-0.92(m, 3H), 0.91-0.67(m, 4H).

Step 2: (7-deuterodispiro [2.0.2.1] hept-7-yl) methanol

Cooling of 7-deuterium dispiro [2.0.2.1] in an ice-water bath]A solution of ethyl heptane-7-carboxylate (9g, 53.82mmol) in tetrahydrofuran (100 mL). Lithium aluminum hydride (2.5g, 65.78mmol) was added in small portions over 5min and the mixture was stirred at ambient temperature under nitrogen atmosphere for 5h the reaction was cooled with an ice water bath for 5min, diluted with ether (200mL) and slowly quenched by addition of saturated aqueous rochelle salt solution (approximately 30mL) until the layers separated significantly. The aqueous layer was extracted with diethyl ether (2X 50 mL). The combined ether layers were washed with brine (50mL), dried over magnesium sulfate and concentrated to give (7-deuterodispiro [2.0.2.1] as a light yellow oil]Hept-7-yl) methanol (4.7g, 98%).¹H NMR (250MHz, chloroform-d) 3.72(s, 2H), 1.00-0.75(m, 4H), 0.74-0.44(m, 4H).

And step 3: 7- (bromomethyl) -7-deuterium-dispiro [2.0.2.1] heptane

A solution of triphenylphosphine (9.38g, 35.65mmol) in dichloromethane (130mL) was cooled to-15 ℃ using a dry ice acetone bath under a nitrogen atmosphere. A solution of bromine (1.85mL, 35.65mmol) in dichloromethane (17mL) was added over 15min, and the reaction mixture was stirred at-15 ℃ for a further 15 min. The mixture was cooled to-30 ℃ and (7-deuterodispiro [2.0.2.1] was added dropwise ]Hept-7-yl) methanol (4.5g, 35.95mmol) and pyridine (2.9mL, 36mmol) in dichloromethane (34 mL). Subsequently, the mixture was warmed to-5 ℃ and stirred for 1 h. The reaction mixture was poured into pentane (1L) such that a white precipitate formed, the solid was filtered off over celite and the filtrate was concentrated (250mbar, using a water bath at about 30 ℃) to give a white solid, pentane (300mL) was added and the mixture was sonicated and filtered, the filtrate was concentrated to give a white solid, which was treated again with pentane (300mL) and filtered, the filtrate was concentrated and chromatographed on silica gel using 0% -5% diethyl ether ^ 5 ^ onThe residue was purified with pentane. The product-containing fractions were concentrated at 300mbar using a 30 ℃ water bath to give 7- (bromomethyl) -7-deuterium-dispiro [2.0.2.1] as a clear oil]Heptane (6.4g, 95%).¹H NMR (250MHz, chloroform-d) 3.49(s, 2H), 1.42-1.17(m, 2H), 1.12-0.81(m, 2H), 0.79-0.64 (m, 2H), 0.62-0.43(m, 2H).

And 4, step 4: 2- (7-deuterodispiro [2.0.2.1] hept-7-yl) acetonitrile

To 7- (bromomethyl) -7-deuterium-dispiro [2.0.2.1]To a solution of heptane (2.3g, 22.02mmol) in dimethyl sulfoxide (30mL) was added sodium cyanide (753mg, 27.53mmol) and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with brine (40mL) and extracted with pentane (2X 50 mL). The combined pentane layers were dried over magnesium sulfate, filtered, and concentrated to give 2- (7-deuterodispiro [2.0.2.1] as a clear oil ]Hept-7-yl) acetonitrile (4g, 87%).¹H NMR (250MHz, chloroform-d) 2.42(s, 2H), 1.04-0.79(m, 4H), 0.79-0.65 (m, 2H), 0.65-0.44(m, 2H).

And 5: 2- (7-deuterodispiro [2.0.2.1] hept-7-yl) acetic acid

To 2- (7-deuterodispiro [2.0.2.1]]To a solution of hept-7-yl) acetonitrile (4g, 29.8mmol) in ethanol (60mL) was added a solution of sodium hydroxide (12g, 300mmol) in water (25mL), and the resulting solution was stirred at 73 ℃ for 15h. The mixture was cooled to room temperature, diluted with water (about 40mL), and extracted with diethyl ether (2X 25 mL). The aqueous phase was adjusted to pH 1 by addition of 6M hydrochloric acid and then extracted with diethyl ether (2 × 40 mL). The combined ether layers were dried over magnesium sulfate, filtered and concentrated to give 2- (7-deuterodispiro [2.0.2.1] as a yellowish solid]Hept-7-yl) acetic acid (2.6g, 57%).¹H NMR (250MHz, chloroform-d) 2.44(s, 2H), 1.03-0.73 (m, 4H), 0.75-0.61(m, 2H), 0.59-0.38(m, 2H).

Step 6: 2- (7-deuterodispiro [2.0.2.1] hept-7-yl) ethanol

A suspension of lithium aluminum hydride (836mg, 22mmol) in tetrahydrofuran (35mL) was cooled in an ice-water bath and 2- (7-deuterodispiro [2.0.2.1] contained was added dropwise over 10min]Hept-7-yl) acetic acid (2.59g, 16.9mmol) in tetrahydrofuran (15mL), the mixture was allowed to warm to ambient temperature and stirred under nitrogen for 15h, the reaction mixture was cooled with an ice-water bath for 5min, then diluted with diethyl ether (60mL) and slowly quenched by addition of saturated aqueous Rochelle salt solution (approximately 40mL) until the layers separated significantly, the lower aqueous layer was extracted with diethyl ether (2X 50mL), the combined ether layers were washed with brine (40mL), dried over magnesium sulfate, filtered and concentrated to give 2- (7-deuterospiro [2.0.2.1] as a light yellow oil ]Hept-7-yl) ethanol (2.4g, quantitative yield).¹H NMR (250MHz, chloroform-d) 3.63(t, J ═ 6.9Hz, 2H), 1.68(t, J ═ 6.8Hz, 2H), 0.94-0.72(m, 4H), 0.72-0.57(m, 2H), 0.57-0.38(m, 2H).

And 7: 3- [2- (7-deuterodispiro [2.0.2.1] hept-7-yl) ethoxy ] pyrazole-1-carboxylic acid tert-butyl ester

To 5-oxo-1H-pyrazole-2-carboxylic acid tert-butyl ester (1.26g, 6.84mmol) and 2- (7-deuterodispiro [2.0.2.1]]Hept-7-yl) ethanol (1g, 6.48mmol), triphenylphosphine (1.78g, 6.8mmol) in tetrahydrofuran (10mL) was added diisopropyl azodicarboxylate (1.34mL, 7.18mmol) dropwise and the reaction mixture was stirred at 50 ℃ for 12 h. The mixture was concentrated and the residue was purified by silica gel column chromatography using a gradient of 100% hexane to 10% ethyl acetate/hexane to give 3- [ (7-deuterodispiro [2.0.2.1] as a white solid]Hept-7-yl) methoxy]Pyrazole-1-carboxylic acid tert-butyl ester (1.75g, 80%).¹H NMR (250MHz, chloroform-d) 7.82(d, J ═ 2.9Hz, 1H), 5.84(d, J ═ 3.0Hz, 1H), 4.26(s, 2H), 1.58(s,9H) 1.44(d, J ═ 6.2Hz, 2H), 0.93-0.73(M, 4H), 0.65(d, J ═ 9.2Hz, 2H), 0.49(d, J ═ 8.8Hz, 2H), ESI-MS M/z calculated 306.2, experimental 307.3(M +1) ⁺(ii) a Retention time: 4.85min (LC method P).

And 8: 3- [2- (7-deuterodispiro [2.0.2.1] hept-7-yl) ethoxy ] -1H-pyrazole

To 3- [ (7-deuterodispiro [2.0.2.1]]Hept-7-yl) methoxy]To a solution of pyrazole-1-carboxylic acid tert-butyl ester (1.75g, 5.72mmol) in dichloromethane (20mL) was added trifluoroacetic acid (10mL), and the resulting mixture was stirred at room temperature for 2h. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give 3- [ (7-deuterodispiro [2.0.2.1] as a white solid]Hept-7-yl) methoxy]-1H-pyrazole (1.2g, quantitative yield).¹H NMR (250MHz, chloroform-d) 7.35(d, J ═ 1.3Hz, 1H), 5.71(d, J ═ 1.4Hz, 1H), 4.12(t, J ═ 7.8Hz, 2H), 1.87(t, J ═ 6.7Hz, 2H), 0.96-0.73(m, 4H), 0.70-0.58(m, 2H), 0.56-0.39(m, 2H). ESI-MS M/z calculated 205.1, Experimental 206.4(M +1)⁺(ii) a Retention time: 2.95min (LC method P).

And step 9: 2-chloro-6- [3- [2- (7-deuterodispiro [2.0.2.1] hept-7-yl) ethoxy ] pyrazol-1-yl ] pyridine-3-carboxylic acid tert-butyl ester

To 2, 6-dichloropyridine-3-carboxylic acid tert-butyl ester (1.44g, 5.8mmol) and 3- [ (7-deuterodispiro [2.0.2.1 ]]Hept-7-yl) methoxy]To a mixture of (E) -1H-pyrazole (1.2g, 3.93mmol) in anhydrous dimethylsulfoxide (24mL) were added potassium carbonate (965mg, 6.97mmol) and 1, 4-diazabicyclo [2.2.2 ]]Octane (130mg, 1.16 mmol.) the resulting mixture was stirred at room temperature under a nitrogen atmosphereThe mixture was then diluted with water (45mL) and stirred for 15 min. The resulting white solid was collected by filtration and washed with water (2 × 20 mL). The solid was dried and purified by silica gel column chromatography using a gradient of 100% hexane to 60% ethyl acetate/hexane to give 2-chloro-6- [3- [ (7-deuterodispiro [2.0.2.1 ] as a white solid]Hept-7-yl) methoxy]Pyrazol-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (1.8g, quantitative yield).¹H NMR (250MHz, chloroform-d) 8.34(dd, J ═ 2.9, 1.1Hz, 1H), 8.18(dd, J ═ 8.4, 1.1Hz, 1H), 7.69(dd, J ═ 8.4, 1.0Hz, 1H), 5.93(dd, J ═ 2.9, 1.1Hz, 1H), 4.24 (s, 2H), 1.74-1.52(M, 10H), 1.48(s, 1H), 0.93-0.77(M, 4H), 0.71-0.60(M, 2H), 0.55-0.44(M, 2H), ESI-MS M/z calculated 416.2, experimental value 417.5(M +1)⁺(ii) a Retention time: 4.87min (LC method P).

Step 10: 2-chloro-6- [3- [2- (7-deuterodispiro [2.0.2.1] hept-7-yl) ethoxy ] pyrazol-1-yl ] pyridine-3-carboxylic acid

To 2-chloro-6- [3- [ (7-deuterodispiro [2.0.2.1]]Hept-7-yl) methoxy]Pyrazol-1-yl]To a solution of pyridine-3-carboxylic acid tert-butyl ester (1.8g, 4.32mmol) in dichloromethane (20mL) was added trifluoroacetic acid (5mL) and the reaction mixture was stirred at room temperature for 15 h. The mixture was concentrated and the residue triturated with a mixture of diethyl ether/pentane (20mL each). The precipitated solid was collected by filtration to give 2-chloro-6- [3- [ (7-deuterodispiro [2.0.2.1] as a white solid]Hept-7-yl) methoxy]Pyrazol-1-yl]Pyridine-3-carboxylic acid (1.19g, 76% yield).¹H NMR (250 MHz, dimethylsulfoxide-d)₆)8.46-8.34(M, 2H), 7.72(dd, J ═ 8.4, 0.8Hz, 1H), 6.17(dd, J ═ 2.9, 0.8Hz, 1H), 4.23(s, 2H), 1.46(s, 2H), 0.92-0.74(M, 4H), 0.64(dd, J ═ 7.6, 4.3Hz, 2H), 0.50(dd, J ═ 7.1, 4.2Hz, 2H), ESI-MS M/z calculated 361.1, experimental 361.3 (M +1)⁺(ii) a Retention time: 3.85min (LC method P).

Step 11: (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [2- (7-deuterospiro [2.0.2.1] hept-7-yl) ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To 2-chloro-6- [3- [2- (7-deuterodispiro [2.0.2.1 ]]Hept-7-yl) ethoxy]Pyrazol-1-yl]To a solution of pyridine-3-carboxylic acid (100 mg, 0.2772mmol) in tetrahydrofuran (2mL) was added carbonyldiimidazole (54mg, 0.3330 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere (balloon) for 2 h. Subsequently, (4S) -2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino group is added]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (121mg, 0.2933mmol) was added followed by 1, 8-diazabicyclo [5.4.0]Undec-7-ene (130 μ L, 0.8693mmol) and the reaction stirred for 16h, the reaction was diluted with ethyl acetate and washed with a 1: 1 saturated solution of ammonium chloride/brine the organics were separated, dried over sodium sulfate, filtered and evaporated the resulting brown residue was purified by silica gel chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate to give (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [2- (7-deuterium dispiro [2.0.2.1 ] as a white solid]Hept-7-yl) ethoxy]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (77mg, 31%). ESI-MS M/z calculated 754.3138, Experimental 755.46(M +1)⁺(ii) a Retention time: 0.67min (LC method G).

Step 12: (14S) -8- (3- {2- [ (7-deuterium) dispiro [2.0.2.1 ]]Hept-7-yl) ethoxy } -1H-pyrazol-1-yl) -12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 253)

Reacting (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [2- (7-deuterium dispiro [2.0.2.1 ]) at room temperature]Hept-7-yl) ethoxy]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]A solution of tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (77mg, 0.1019mmol) in dichloromethane (400 μ L) and trifluoroacetic acid (100 μ L, 1.307mmol) was stirred for 4h the solvent was removed by evaporation and the resulting residue was dissolved in ethyl acetate. Washed with 2mL of saturated solution of sodium bicarbonate and the organic layer was collected and the solvent was evaporated. The resulting thick oil was further dried under vacuum the resulting residue was dissolved in dimethyl sulfoxide (5mL) and added

Molecular sieves and stirring the reaction mixture for 10min then cesium fluoride (49mg, 0.3226mmol) and potassium carbonate (47mg, 0.3401mmol) were added and the reaction mixture was heated at 150 ℃ for 16h the reaction mixture was filtered through Whatman filter disc (puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS method using a double gradient run of 50% -99% mobile phase B over 15.0min (mobile phase a ═ water (0.05% hydrochloric acid), mobile phase B ═ acetonitrile) to give (14S) -8- (3- {2- [ (7-deuterium) dispiro [2.0.2.1 ] as a white solid ]Hept-7-yl]Ethoxy } -1H-pyrazol-1-yl) -12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 253) (26.9mg, 43%).¹H NMR (400 MHz, chloroform-d) 8.18(d, J ═ 2.8Hz, 1H), 8.05(d, J ═ 8.3Hz, 1H), 7.58-7.47(m, 2H), 7.26(s, 1H), 6.56(d, J ═ 8.2Hz, 1H), 5.89(d, J ═ 2.8Hz, 1H), 4.71(s, 1H), 4.24 (t, J ═ 6.8Hz, 2H), 3.85(d, J ═ 37.1Hz, 1H), 3.32(s, 1H), 3.15(d, J ═ 13.6Hz, 1H), 3.02(d, J ═ 27.8Hz, 1H), 2.56(s, 1H), 2.06(t, J ═ 10.0, 1H), 1.02 (d, J ═ 27.8Hz, 1H), 2.56(s, 1H), 2.06(t, J ═ 10.0, 1H), 1H, 4.75 (m, 0, 5H), 4.75 (m, 0H), 5H). ESI-MS M/z calculated 618.2847, Experimental 619.15(M +1)⁺(ii) a Retention time: 1.96min (LC method G).

Example 80: preparation of (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-20-hydroxy-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 254)

Step 1: 3-benzyloxy-6-bromo-2-nitro-pyridine

A solution of 6-bromo-2-nitro-pyridin-3-ol (12g, 54.796mmol) in anhydrous N, N-dimethylformamide (100mL) was cooled with an ice-water bath under nitrogen sodium hydride (2.49g, 62.256mmol, 60% in mineral oil) was added in one portion and the reaction stirred for 10 min. Subsequently, benzyl chloride (7.5900g, 6.9mL, 59.961mmol) was added and the reaction was allowed to warm to room temperature the reaction was stirred at 60 ℃ for two days. The reaction was cooled to room temperature, quenched with water (200mL) and extracted with ethyl acetate (5 × 100 mL). The combined organic layers were washed with brine (3 × 70mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure the residue was triturated in a 4: 1 heptane/ethyl acetate mixture (50mL) the resulting solid was filtered, washed with heptane and dried under reduced pressure to give 3-benzyloxy-6-bromo-2-nitro-pyridine as a yellow solid (13.643g, 81%).¹H NMR (300MHz，CDCl₃)5.23(s, 2H), 7.33-7.43(M, 6H), 7.60(d, J ═ 8.7Hz, 1H.) ESI-MS M/z calcd for 307.9797, experimental value 309.0(M +1)⁺(ii) a Retention time: 2.155min (LC method I).

Step 2: 3- [ (5-benzyloxy-6-nitro-2-pyridyl) sulfanyl ] propionic acid 2-ethylhexyl ester

To a degassed solution of 3-benzyloxy-6-bromo-2-nitro-pyridine (13.143g, 42.518mmol) and diisopropylethylamine (11.130g, 15mL, 86.117mmol) in anhydrous toluene (260mL) was added Xantphos (1.49g, 2.5751mmol) with a mixture of N, N-dimethylformamide and N, N-dimethylformamide, Tris (dibenzylideneacetone) dipalladium (0) (1.155g, 1.2613 mmol) and diisopropylethylamine (11.130g, 15mL, 86.117 mmol). The reaction was fitted with a reflux condenser and stirred at 110 ℃ overnight the reaction was cooled to room temperature, filtered and washed with ethyl acetate the filtrate was concentrated under reduced pressure and the crude product was purified by flash chromatography on silica gel. While filling with heptane (gradient from 100% heptane to 30% ethyl acetate/heptane) to give 3- [ (5-benzyloxy-6-nitro-2-pyridinyl) sulfanyl]2-ethylhexyl propionate (18.977g, 95%). ESI-MS M/z calculated 446.1875, Experimental 447.2(M +1)⁺(ii) a Retention time: 2.262min (LC method I).

And step 3: 3- [ (5-benzyloxy-6-nitro-2-pyridyl) sulfonyl ] propionic acid 2-ethylhexyl ester

To 3- [ (5-benzyloxy-6-nitro-2-pyridyl) sulfanyl group]To a solution of 2-ethylhexyl propionate (19.65g, 44.003 mmol) in dichloromethane (170mL) was added m-chloroperbenzoic acid (19.795g, 88.326 mmol) in portions. The reaction was exothermic and became cloudy. The reaction was stirred at room temperature overnight. Ethyl acetate (200mL) was added and the reaction was washed successively with 5% aqueous sodium bicarbonate (200mL) and 0.5M aqueous sodium hydroxide (2X 200 mL.) the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 3- [ (5-benzyloxy-6-nitro-2-pyridinyl) sulfonyl as a yellow oil ]2-ethylhexyl propionate (20.905g, 99%).¹H NMR(300MHz，CDCl₃)0.83-0.94(m, 6H), 1.22-1.32(m, 6H), 1.50-1.64 (m, 2H), 2.87(t, J ═ 7.6Hz, 2H), 3.70(t, J ═ 7.6Hz, 2H), 4.01(dd, J ═ 6.0, 2.2Hz, 2H), 5.37(s, 2H), 7.35-7.48(m, 5H), 7.69(d, J ═ 8.5Hz, 1H), 8.22(d, J ═ 8.5Hz, 1H). ESI-MS M/z calculated 478.1774, Experimental 367.1(M-C8H16+1)⁺(ii) a Retention time: 2.419min (LC method I).

And 4, step 4: 3- [ (6-amino-5-benzyloxy-2-pyridyl) sulfonyl ] propionic acid 2-ethylhexyl ester

To 3- [ (5-benzyloxy-6-nitro-2-pyridyl) sulfonyl group]To a solution of 2-ethylhexyl propionate (6.24g, 13.039 mmol) in ethanol (250mL) and water (50mL) was added iron (2.525g, 45.214mmol) and ammonium chloride (2.021g, 37.782 mmol). The reaction was stirred at 100 ℃ for 1.5h, cooled to room temperature, filtered through celite, and washed with dichloromethane (200 mL.) the filtrate was concentrated under reduced pressure, diluted in dichloromethane (100mL), and washed with water (2X 50 mL.) the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3- [ (6-amino-5-benzyloxy-2-pyridinyl) sulfonyl) as a yellow oil]2-ethylhexyl propionate (6.25g, quantitative yield). ESI-MS M/z calculation 448.2032, Experimental 449.3(M +1) ⁺(ii) a Retention time: 2.565min (LC method N).

And 5: 3- [ (5-benzyloxy-6-fluoro-2-pyridinyl) sulfonyl ] propionic acid 2-ethylhexyl ester

3- [ (6-amino-5-benzyloxy-2-pyridyl) sulfonyl group]A solution of 2-ethylhexyl propionate (6.25g, 13.933 mmol) in pyridine containing hydrogen fluoride (71.500g, 65mL, 721.45mmol) was cooled to-40 ℃. The resulting red solution was treated with sodium nitrite (1.92g, 27.828mmol) and allowed to warm to room temperature. The mixture was neutralized by careful addition of aqueous sodium bicarbonate solution and extracted with ethyl acetate (4 × 150 mL.) the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure the crude product was purified by flash chromatography on silica gel loaded with heptane (gradient of 100% heptane to 40% ethyl acetate/heptane) to give 3- [ (5-benzyloxy-6-fluoro-2-pyridinyl) sulfonyl as a yellow oil]2-ethylhexyl propionate (3.691g, 59%). ESI-MS M/z Calcd 451.1829, Experimental 452.2(M +1)⁺(ii) a Retention time: 2.648min (LC method O).

Step 6: 5-benzyloxy-6-fluoro-pyridine-2-sulfonamide

To 3- [ (5-benzyloxy-6-fluoro-2-pyridyl) sulfonyl group]To a solution of 2-ethylhexyl propionate (3.09g, 6.8431mmol) in dimethyl sulfoxide (19mL) was added 1, 8-diazabicyclo (5.4.0) undec-7-ene (2.0200g, 2mL, 13.269 mmol). The reaction was stirred at room temperature for 1h, and a solution of hydroxylamine-O-sulfonic acid (3.873g, 34.246 mmol) and sodium acetate (2.246g, 27.379mmol) in water (12mL) was added. The reaction was stirred at room temperature for 1h, diluted with water (50mL) and extracted with ethyl acetate (3X 20 mL.) the combined organic layers were washed with brine (30mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure the crude product was purified by flash chromatography on silica gel loaded with heptane (a gradient of heptane/ethyl acetate 100: 0 to 50: 50) to give 5-benzyloxy-6-fluoro-pyridine-2-sulfonamide as a white solid (1.58g, 80%).¹H NMR (300MHz, dimethylsulfoxide-d)₆)5.33 (s, 2H), 7.34-7.52(m, 7H), 7.79-7.95(m, 2H). 19F NMR (282MHz, dimethyl sulfoxide-d 6) -83.6(d, J ═ 12.2Hz, 1F.) ESI-MS M/z calculated 282.0474, experimental 283.1(M +1)⁺(ii) a Retention time: 2.33min (LC method H).

And 7: (4S) -4- [3- [ (3-benzyloxy-6-sulfamoyl-2-pyridyl) amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred solution of (4S) -4- (3-aminopropyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.7801mmol) in anhydrous dimethyl sulfoxide (2.5mL) under nitrogen was added in order 5-benzyloxy-6-fluoro-pyridine-2-sulfonamide (221mg, 0.7829mmol) and N, N-diisopropylethylamine (200 μ L, 1.148mmol). The resulting yellow solution was stirred at 85 ℃ for 9h, then at 40 ℃ for 13hThe ester (60mL) was diluted and water (50mL) was added, the solution was then acidified with 10% citric acid (10mL) and the layers were separated, the organic phase was washed with brine (20mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a yellow viscous material the crude reaction mixture was purified by silica gel chromatography (40g silica gel, eluting over 30min with a gradient of 10-60% ethyl acetate/hexanes) to give the desired (4S) -4- [3- [ (3-benzyloxy-6-sulfamoyl-2-pyridyl) amino group as a white foam]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (370mg, 91%). ESI-MS M/z calculated 518.2563, experimental 519.4(M +1)⁺(ii) a Retention time: 1.75min (LC method B).

And 8: (4S) -4- [3- [ [ 3-benzyloxy-6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1] hept-7-ylethoxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To 2-chloro-6- [3- (2-dispiro [2.0.2.1 ]]Hept-7-ylethoxy) pyrazol-1-yl]A stirred solution of pyridine-3-carboxylic acid (150mg, 0.4169mmol) in anhydrous tetrahydrofuran (3mL) was added carbonyldiimidazole (75mg, 0.4625mmol) and stirring was continued at ambient temperature under nitrogen for 2 h. To the reaction was added (4S) -4- [3- [ (3-benzyloxy-6-sulfamoyl-2-pyridyl) amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (196mg, 0.3779mmol) in anhydrous tetrahydrofuran (1mL) followed by addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (220 μ L, 1.471mmol) and the mixture was stirred at ambient temperature for 15 h the volatiles were removed under reduced pressure and the residue was dissolved in ethyl acetate (20mL) and water (10mL) and the mixture was slowly acidified with hydrochloric acid (1.6mL, 1.0M, 1.600mmol) to about pH 4.0 the layers were separated and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic phases were washed with brine (15mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure the crude material was purified by silica gel chromatography (24g silica gel column, gradient of 0-70% ethyl acetate/hexane over 35min) to give (4S) -4- [3- [ [3-Benzyloxy-6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1 ] ]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (171mg, 37%). ESI-MS M/z calculated 859.34937, Experimental 860.5(M +1)⁺(ii) a Retention time: 2.49min (LC method G).

And step 9: n- [ [ 5-benzyloxy-6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] propylamino ] -2-pyridinyl ] sulfonyl ] -2-chloro-6- [3- (2- (dispiro [2.0.2.1] hept-7-ylethoxy) pyrazol-1-yl ] pyridine-3-carboxamide (trifluoroacetate)

Reaction under nitrogen at ambient temperature to (4S) -4- [3- [ [ 3-benzyloxy-6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]To a stirred solution of tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (75mg, 0.08716mmol) in anhydrous dichloromethane (3mL) was added trifluoroacetic acid (350 μ L, 4.543 mmol). The orange solution was stirred for 1h, followed by removal of volatiles under reduced pressure. Toluene (20mL) was added to the residue and concentrated to dryness under reduced pressure. The process was repeated again to remove any residual trifluoroacetic acid and finally dried in vacuo for 2h to obtain crude N- [ [ 5-benzyloxy-6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] amine ]Propylamino group]-2-pyridyl]Sulfonyl radical]-2-chloro-6- [3- (2-dispiro [2.0.2.1 ]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carboxamide (trifluoroacetate) (66mg, 87%). this material was used in the next step without further purification ESI-MS calcd for 759.29694, experimental 760.5(M +1)⁺(ii) a Retention time: 1.43min (LC method B).

Step 10: (14S) -20- (benzyloxy) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione

A20 mL vial was charged with N- [ [ 5-benzyloxy-6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] in that order]Propylamino group]-2-pyridyl]Sulfonyl radical]-2-chloro-6- [3- (2-dispiro [2.0.2.1 ]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carboxamide (trifluoroacetate salt) (60mg, 0.06862mmol), potassium carbonate (60mg, 0.4341 mmol), cesium fluoride (21mg, 0.1382mmol) and anhydrous dimethyl sulfoxide (4mL) the vial was purged with a stream of nitrogen for 2min, capped and stirred at 160 ℃ for 15h the reaction was cooled to ambient temperature and the heterogeneous mixture was diluted with ethyl acetate (30mL) and water (20mL) and acidified with hydrochloric acid (1.0mL, 1.0M, 1.000mmol), the layers were separated and the aqueous layer was extracted with additional ethyl acetate (20mL), the combined organics were washed with brine (20mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by silica gel chromatography (0% -10% methanol/dichloromethane over 30min) to give (14S) -20- (benzyloxy) -8- [3- (2- { dispiro [2.0.2.1 ] as a white solid ]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (41mg, 83%). ESI-MS M/z calculated 723.3203, Experimental 724.5(M +1)⁺(ii) a Retention time: 2.27min (LC method G).

Step 11: (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-20-hydroxy-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 254)

To (14S) -20- (benzyloxy) -8- [3- (2- { dispiro [2.0.2.1 ] under nitrogen]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]To a stirred solution of tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (30mg, 0.04144mmol) in dry methanol (6mL) was added 10% palladium on carbon (moist, Degussa) (16mg, 0.01503 mmol). The heterogeneous mixture was stirred at ambient temperature under an atmosphere of hydrogen (from a balloon) for 2.5 h.the hydrogen balloon was removed and the flask was purged with nitrogen and the black heterogeneous reaction mixture was filtered through a pad of celite the filtrate was concentrated under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.5mL) and filtered through a Whatman 0.45 μm PTFE syringe filter plate using preparative reverse phase HPLC-MS [ Luna C sold by Phenomenex ₁₈(2) Column (75X 30 mm, 5 μm particle size) (pn: 00C-4252-U0-AX), (15 min, double gradient run with 30% -99% acetonitrile/water (no modifier)]The sample was purified to give (14S) -8- [3- (2- { dispiro [2.0.2.1 ] as a pale blue-green solid]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-20-hydroxy-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 254) (20mg, 75%).¹H NMR (400MHz, methanol-d)₄)8.24(d, J ═ 2.8Hz, 1H), 7.82(d, J ═ 8.3Hz, 1H), 7.19(d, J ═ 7.8Hz, 1H), 6.97(d, J ═ 8.3Hz, 1H), 6.89(d, J ═ 7.8Hz, 1H), 5.94(d, J ═ 2.7Hz, 1H), 4.24(t, J ═ 6.6Hz, 2H), 4.04(t, J ═ 13.2Hz, 1H), 3.37-3.32 (m, 1H), 3.14(dt, J ═ 13.6, 4.4Hz, 1H), 2.86(t, J ═ 10.4Hz, 1H), 2.30-2.13(m, 1H), 1.88(q, 7.6, 4.4Hz, 1H), 6.78 (m, 1H), 3.78H, 6H, 1H, 8.8H, 6H, 1H, 3.78 (m, 1H), 3.6H, 8H, 6H, 1H, 3.78 (m, 6H, 1H, 3.78, 1H, 6H, 1H, 8H, 6H, 1H, 8H, 6H, 1H, 6H, 3.6H, 6H, 1H, 3.6H, 4.6, 3.3Hz, 2H), 0.56-0.47(m, 2H). ESI-MS M/z calculated 633.2733, Experimental 634.4(M +1) ⁺(ii) a Retention time: 1.9min (LC method G).

Example 81: preparation of (14S) -20-hydroxy-12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 255)

Step 1: (4S) -4- [3- [ [ 3-benzyloxy-6- [ [ 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]To a stirred solution of pyridine-3-carboxylic acid (150mg, 0.3849mmol) in anhydrous tetrahydrofuran (3mL) was added carbonyldiimidazole (68mg, 0.4194mmol) and stirring was continued under nitrogen at ambient temperature for 2h (4S) -4- [3- [ (3-benzyloxy-6-sulfamoyl-2-pyridyl) amino]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (180mg, 0.3470mmol) in anhydrous tetrahydrofuran (1mL) followed by addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (200. mu.L, 1.337mmol) and the mixture was stirred at ambient temperature for 15 h. The volatiles were removed under reduced pressure and the residue was dissolved in ethyl acetate (20mL) and water (10mL) and the mixture was slowly acidified to about pH 4.0 with hydrochloric acid (1.5mL, 1.0M, 1.500 mmol). The layers were separated and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic z phases were washed with brine (15mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (gradient of 0% to 70% ethyl acetate/hexane over 35min) to give (4S) -4- [3- [ [ 3-benzyloxy-6- [ [ 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] methyl ] phenyl ] ethyl acetate as a white solid ]Propoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (170mg, 22%). ESI-MS M/z calculated 889.3211, experimental 890.5(M +1)⁺(ii) a Retention time: 2.32min (LC method G).

Step 2: n- [ [ 5-benzyloxy-6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] propylamino ] -2-pyridinyl ] sulfonyl ] -2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carboxamide (trifluoroacetate)

To (4S) -4- [3- [ [ 3-benzyloxy-6- [ [ 2-chloro-6- [3-3- [1- (trifluoromethyl) cyclopropyl ] at ambient temperature under nitrogen]Propoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (80mg, 0.08985mmol) to a stirred solution in anhydrous dichloromethane ((2.0mL) was added trifluoroacetic acid (350 μ L, 4.543mmol), -the orange solution was stirred for 1h and then the volatiles were removed under reduced pressure-toluene (20mL) was added to the residue and then concentrated to dryness under reduced pressure-the process was repeated again to remove any residual trifluoroacetic acid and finally dried under vacuum for 2h to obtain crude N- [ [ 5-benzyloxy-6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] ester ]Propylamino group]-2-pyridyl]Sulfonyl radical]-2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxamide (trifluoroacetate) (81 mg, 100%). This material was used directly in the next step without any purification. ESI-MS M/z calculated 789.2687, Experimental 790.5(M +1)⁺(ii) a Retention time: 1.9min (LC method B).

And step 3: (14S) -20- (benzyloxy) -12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Propoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione

A20 mL vial was charged with N- [ [ 5-benzyloxy-6- [3- (5, 5-dimethylpyrrolidin-3-yl) in that order]Propylamino group]-2-pyridyl]Sulfonyl radical]-2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxamide (trifluoroacetate) (80mg, 0.08846mmol), potassium carbonate (75mg, 0).5427mmol), cesium fluoride (27mg, 0.1777mmol) and anhydrous dimethylsulfoxide (5 mL). The vial was purged with a stream of nitrogen for 2min, capped and stirred at 160 ℃ for 15 h. The reaction was cooled to ambient temperature and the heterogeneous mixture was diluted with ethyl acetate (30 mL) and water (20mL) and acidified with hydrochloric acid (1.5mL, 1.0M, 1.500mmol) the layers were separated and the aqueous layer was extracted with ethyl acetate (20mL) the combined organics were washed with brine (20mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure the crude residue was purified by silica gel chromatography (0% -10% methanol/dichloromethane gradient over 30min) to give (14S) -20- (benzyloxy) -12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl) -propyl ] as a white solid ]Propoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (55mg, 82%). ESI-MS M/z calculated 753.29205, Experimental 754.5(M +1)⁺(ii) a Retention time: 2.11min (LC method G).

And 4, step 4: (14S) -20-hydroxy-12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Propoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 255)

To (14S) -20- (benzyloxy) -12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl) under nitrogen]Propoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]A stirred solution of tetracos-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (42mg, 0.05572mmol) in dry methanol (5 mL) was added 10% palladium on carbon (moist, Degussa) (8mg, 0.007517 mmol.) the heterogeneous mixture was stirred under hydrogen (from balloon) at ambient temperature for 2.5h the hydrogen balloon was removed and the flask was purged with nitrogen and the black heterogeneous reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure, and the residue was removed The residue was dissolved in dimethyl sulfoxide (1.5mL) and filtered through a Whatman 0.45 μm PTFE syringe filter. Use preparative reverse phase HPLC-MS [ Luna C sold by Phenomenex₁₈(2) Column (75X 30 mm, 5 μm particle size) (pn: 00C-4252-U0-AX), (15 min, double gradient run with 30% -99% acetonitrile/water (no modifier)]Purifying the sample to obtain (14S) -20-hydroxy-12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl ] as a light blue-green solid]Propoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (42 mg, 0.05572mmol) (compound 255) (27mg, 72%).¹H NMR (400MHz, methanol-d)₄) 8.25(d, J ═ 2.8Hz, 1H), 7.82(d, J ═ 8.1Hz, 1H), 7.19(d, J ═ 7.8Hz, 1H), 6.98(d, J ═ 8.3Hz, 1H), 6.89(d, J ═ 7.8Hz, 1H), 5.97(d, J ═ 2.9Hz, 1H), 4.24(t, J ═ 6.1Hz, 2H), 4.03(t, J ═ 12.8Hz, 1H), 3.42-3.32(m, 1H), 3.14(dt, J ═ 13.9, 4.4Hz, 1H), 2.85(s, 1H), 2.32-2.09(m, 1H), 1.99-1.83(m, 4H), 1.74-1.74 (m, 1H), 0.66 (d, 3.66H, 1H), 3.66 (m, 1H), 3.0.66H), 3.0.3.3.3.6 (d, 1H), 3.0Hz, 2H). ESI-MS M/z calculated 663.24506, Experimental 664.4(M +1) ⁺(ii) a Retention time: 1.7min (LC method G).

Example 82: preparation of (14S) -8- (3-hydroxy-1H-pyrazol-1-yl) -12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 256)

Step 1: (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [ (2, 2, 3, 3-tetramethylcyclopropyl) methoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- [ (2, 2, 3, 3-tetramethylcyclopropyl) methoxy group]Pyrazol-1-yl]Pyridine-3-carboxylic acid (200mg, 0.5717mmol) and carbonyldiimidazole (116mg, 0.7154mmol) (newly recrystallized from tetrahydrofuran, washed with low temperature ether and dried under high vacuum) were combined in tetrahydrofuran (2mL) and stirred at room temperature for 2 h. Subsequently, (4S) -2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino group is added]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (275mg, 0.6666mmol) followed by the addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (500 μ L, 3.343mmol) and the reaction stirred at room temperature for 14h the reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate the organic layer was washed with brine, dried (magnesium sulfate), filtered and concentrated the resulting brown residue was purified by silica gel column chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate to give (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [ (2, 2, 3, 3-tetramethylcyclopropyl) methoxy ] as an off-white solid ]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (172mg, 40%). ESI-MS calculated M/z 743.3232, Experimental 744.45(M +1)⁺(ii) a Retention time: 0.97min (LC method A).

Step 2: (14S) -8- (3-hydroxy-1H-pyrazol-1-yl) -12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 256)

Reacting (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [ (2, 2, 3, 3-tetramethylcyclopropyl) methoxy group at room temperature]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]Solution of tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (172mg, 0.2311mmol) in dichloromethane (1.5mL) and trifluoroacetic acid (500. mu.L, 6.534mmol) was stirredStirring for 4 h. The solvent was removed and the residue was dissolved in ethyl acetate. Washed with 2mL of saturated aqueous sodium bicarbonate solution and the organic layer was collected and the solvent removed in vacuo. The residue was dissolved in dimethyl sulfoxide (10 mL) and added

Molecular sieves and stirring the reaction mixture for 10min then cesium fluoride (115 mg, 0.7571mmol) and potassium carbonate (107mg, 0.7742mmol) were added and the reaction mixture was heated at 150 ℃ for 16 h. The reaction mixture was cooled to room temperature and filtered through celite, and a saturated solution of ammonium chloride was added to the filtrate. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. By the reverse phase HPLC-MS method, using Luna C sold by Phenomenex ₁₈(2) Column (75 × 30mM, 5 μm particle size) (pn: 00C-4252-U0-AX) and the resulting brown residue was purified by 15min of a double gradient run of 30% to 99% mobile phase B (mobile phase a ═ water (5mM hydrochloric acid), mobile phase B ═ acetonitrile ═ 50 mL/min, injection volume of 950 μ L and column temperature of 25 ℃) to give (14S) -8- (3-hydroxy-1H-pyrazol-1-yl) -12, 12-dimethyl-2 λ as an off-white solid⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 256) (19.5mg, 17%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.58(s, 1H), 10.63(s, 1H), 8.22(d, J ═ 2.7Hz, 1H), 7.87(d, J ═ 7.8Hz, 1H), 7.65(s, 1H), 7.13(d, J ═ 6.9 Hz, 1H), 6.94(d, J ═ 8.2Hz, 1H), 6.79(s, 1H), 6.00(d, J ═ 2.7Hz, 1H), 4.02(d, J ═ 12.8Hz, 1H), 3.27(d, J ═ 5.2Hz, 1H), 3.04(d, J ═ 13.3Hz, 1H), 2.90-2.73(M, 0H), 2.18(d, J ═ 4.1, 1H), 1.95(d, J ═ 13.3Hz, 1H), 1.86 (ddh, 1H, 5.3H), 3H, 1H, 3H, 3.18 (M, 3H, 19, 11, 3H, 11, 1H), 3H, 11, 3H, 11H, 49 (M, 3H, M, 3H), 3H, M, 3, M. ⁺(ii) a Retention time: 1.47min (LC method B).

Example 83: preparation of (14S) -8- [3- (2- { dispiro [2.0.2.1]]Hept-7-yl } -2-hydroxyethoxy) -1H-pyrazole-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 257)

Step 1: 3- (2-Dispiro [2.0.2.1] hept-7-yl-2-oxo-ethoxy) pyrazole-1-carboxylic acid tert-butyl ester

A solution of n-BuLi (16mL, 2.5M in hexanes, 40.000mmol) was added to a solution of diisopropylamine (4.0432g, 5.6mL, 39.957mmol) in tetrahydrofuran (50mL), pre-cooled to-30 ℃ (flask 1.) the mixture was stirred in an ice-water bath for 20min before cooling to-78 ℃]Heptane-7-carboxylic acid ethyl ester (1.66g, 9.9869mmol) was dissolved in 100mL tetrahydrofuran. Methyl chloro (iodo) chloride (8.8112g, 3.7mL, 48.956mmol) was added and the solution was cooled to-78 ℃ under a nitrogen balloon (flask 2.) the contents of flask 1 were transferred (very quickly dropwise) to flask 2 via a cannula over about 15 min. The resulting mixture was further stirred at-78 ℃ for 1 h. A mixture of acetic acid/tetrahydrofuran (15mL/15 mL) was added dropwise the dry ice bath was removed and the mixture was warmed to about 0 ℃ before it was partitioned between water and ethyl acetate. Separate the layers and wash the aqueous layer again with ethyl acetate the combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated the residue is dissolved in N, N-dimethylformamide (15mL) at room temperature, tert-butyl 3-hydroxypyrazole-1-carboxylate (810mg, 4.3976mmol) is added followed by potassium carbonate (1.25g, 9.0445mmol) and potassium iodide (62mg, 0.3735mmol) the mixture is stirred at 60 ℃ for 48h then cooled to room temperature and diluted with ethyl acetate/water (30 mL each), the layers are separated and the aqueous layer is extracted once more with ethyl acetate (20mL), the combined organic layers are washed with water (20mL), brine, dried over anhydrous sodium sulfate and concentrated The residue was purified by silica gel chromatography using a gradient of 5% to 40% ethyl acetate/hexane the desired product was obtained as a white solid (less polar isomer): 3- (2-dispiro [2.0.2.1]]Hept-7-yl-2-oxo-ethoxy) pyrazole-1-carboxylic acid tert-butyl ester (620mg, 47%).¹H NMR (250 MHz, chloroform-d) 7.85(s, 1H), 5.96(s, 1H), 4.95(s, 2H), 2.62(s, 1H), 1.60(s 9H), 1.34-1.16(M, 2H), 1.14-0.63(M, 6H). ESI-MS M/z Calculation 318.158, Experimental 319.5 (M +1)⁺(ii) a Retention time: 3.59min (LC method P).

Step 2: 3- (2-Dispiro [2.0.2.1] hept-7-yl-2-hydroxy-ethoxy) pyrazole-1-carboxylic acid tert-butyl ester

Mixing 3- (2-dispiro [2.0.2.1]]Hept-7-yl-2-oxo-ethoxy) pyrazole-1-carboxylic acid tert-butyl ester (620mg, 1.7527mmol) was dissolved in ethanol (10mL) and the mixture was cooled in an ice-water bath sodium borohydride (66.309mg, 0.0702mL, 1.7176mmol) was added. After 5min, methanol (0.5mL) was added. The mixture was stirred at room temperature for 1 h. It was then quenched with saturated aqueous ammonium chloride solution and partitioned between ethyl acetate and water (20 mL each). The layers were separated and the organic layer was filtered through a pad of anhydrous sodium sulfate and concentrated. Crude 3- (2-dispiro [2.0.2.1] ]Hept-7-yl-2-hydroxy-ethoxy) pyrazole-1-carboxylic acid tert-butyl ester (600mg, 91%) was used in the next step without further purification ESI-MS M/z calculated 320.1736, experimental 321.3(M +1)⁺(ii) a Retention time: 3.44min (LC method P).

And step 3: tert-butyl- [ 1-dispiro [2.0.2.1] hept-7-yl-2- (1H-pyrazol-3-yloxy) ethoxy ] -dimethyl-silane

Mixing 3- (2-dispiro [2.0.2.1]]Hept-7-yl-2-hydroxy-ethoxy) pyrazole-1-carboxylic acid tert-butyl ester (300mg, 0.8896mmol) was dissolved in dichloromethane (10mL) and blown under a nitrogen balloon at iceThe mixture was stirred in a water bath 2, 6-lutidine (686.96mg, 0.75mL, 6.3469mmol) was added followed by TBDMSOTf (1.2408g, 1.1mL, 4.6001mmol) and the mixture stirred for 30 min. 2, 6-lutidine (551mg, 0.6mL, 5mmol) was added again followed by TBDMSOTf (1.2408g, 1.1mL, 4.6001mmol). The mixture was stirred for 12h, then diluted with dichloromethane (40mL) and treated with a saturated aqueous solution of sodium bicarbonate (30 mL). The layers were separated and the dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated the residue was purified by silica gel chromatography using a gradient of 0% to 30% ethyl acetate/hexanes to give tert-butyl- [ 1-dispiro [2.0.2.1] as a colorless oil ]Hept-7-yl-2- (1H-pyrazol-3-yloxy) ethoxy]Dimethyl-silane (300mg, 81%). ESI-MS M/z calculated 334.2077, Experimental value 335.6(M +1)⁺(ii) a Retention time: 4.55min (LC method P).

And 4, step 4: 6- [3- [2- [ tert-butyl (dimethyl) silyl ] oxy-2-dispiro [2.0.2.1] hept-7-yl-ethoxy ] pyrazol-1-yl ] -2-chloro-pyridine-3-carboxylic acid tert-butyl ester

Reacting tert-butyl- [ 1-dispiro [2.0.2.1] at room temperature]Hept-7-yl-2- (1H-pyrazol-3-yloxy) ethoxy]-dimethyl-silane (300mg, 0.8071mmol) dissolved in dimethyl sulfoxide (8mL) Tert-butyl 2, 6-dichloropyridine-3-carboxylate (210mg, 0.8464mmol) was added followed by potassium carbonate (138mg, 0.9985mmol) and 1, 4-diazabicyclo [2.2.2 mmol]Octane (18mg, 0.1605 mmol). The mixture was stirred at room temperature for 24 h. Ethyl acetate (ca. 25mL) was added followed by water (ca. 20 mL). The layers were separated and the aqueous layer was extracted once more with ethyl acetate (about 20 mL). The combined organics were concentrated and the residue was purified by silica gel chromatography using a 0% to 10% ethyl acetate/hexanes gradient to give 6- [3- [2- [ tert-butyl (dimethyl) silyl ] silane as a white solid]Oxy-2-dispiro [2.0.2.1]Hept-7-yl-ethoxy]Pyrazol-1-yl]-2-chloro-pyridine-3-carboxylic acid tert-butyl ester (490mg, 100%). ¹H NMR (250MHz, chloroform-d) 8.35(dd, J ═ 2.8, 0.9Hz, 1H), 8.19(dd, J ═ 8.4, 0.9Hz, 1H), 7.68(dd, J ═ 8.4, 0.9Hz, 1H), and，J＝8.4，0.9Hz，1H)，5.93(dd，J＝2.9，0.9Hz，1H)，4.17(dd，J＝5.5，0.9 Hz，2H)，4.01-3.80(m，1H)，1.78-1.43(m，13H)，1.38-1.16(m，4H)，1.15-0.45 (m，22H)，0.20--0.01(m，6H)。

and 5: 6- [3- [2- [ tert-butyl (dimethyl) silyl ] oxy-2-dispiro [2.0.2.1] hept-7-yl-ethoxy ] pyrazol-1-yl ] -2-chloro-pyridine-3-carboxylic acid

Reacting 6- [3- [2- [ tert-butyl (dimethyl) silyl]Oxy-2-dispiro [2.0.2.1]Hept-7-yl-ethoxy]Pyrazol-1-yl]Tert-butyl-2-chloro-pyridine-3-carboxylate (200mg, 0.3296mmol) was dissolved in dichloromethane (4mL) and cooled in an ice-water bath. Triethylamine (200.11mg, 0.2756mL, 1.9776mmol) was added followed by TBDMSOTf (609.88mg, 2.3072 mmol). The mixture was stirred at room temperature for 5h and diluted with dichloromethane (10mL) water (about 10mL) was added and the layers were separated. The dichloromethane layer was concentrated and the residue was purified by silica gel chromatography using a 0% to 10% methanol/dichloromethane gradient to give 6- [3- [2- [ tert-butyl (dimethyl) silyl]Oxy-2-dispiro [2.0.2.1]Hept-7-yl-ethoxy]Pyrazol-1-yl]-2-chloro-pyridine-3-carboxylic acid (50 mg, 22%).¹H NMR (250MHz, chloroform-d) 8.49-8.17(m, 2H), 7.70(d, J ═ 8.4Hz, 1H), 5.94(d, J ═ 2.9Hz, 1H), 4.16(d, J ═ 5.4Hz, 2H), 3.89(dt, J ═ 8.6, 5.4Hz, 1H), 1.65(t, J ═ 7.6Hz, 1H), 1.12-0.41(m, 19H), 0.06(d, J ═ 2.2Hz, 6H). ESI-MS M/z calculated 489.1851, Experimental 490.7(M +1) ⁺(ii) a Retention time: 4.53min (LC method P).

Step 6: (4S) -4- [3- [ [6- [ [6- [3- [2- [ tert-butyl (dimethyl) silyl ] oxy-2-dispiro [2.0.2.1] hept-7-yl-ethoxy ] pyrazol-1-yl ] -2-chloro-pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

6- [3- [2- [ tert-butyl (dimethyl) silyl ] silane at room temperature under a nitrogen balloon]Oxy-2-dispiro [2.0.2.1]Hept-7-yl-ethoxy]Pyrazol-1-yl]-2-chloro-pyridine-3-carboxylic acid (750mg, 1.5304mmol) was dissolved in tetrahydrofuran (5mL) carbonyldiimidazole (345mg, 2.0851mmol) was added in one portion. The reaction was stirred for 4h. in a separate flask, (4S) -2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino was weighed]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (695mg, 1.6847mmol) and tetrahydrofuran (5mL) was added followed by 1, 8-diazabicyclo [ 5.4.0%]Undec-7-ene (249.90mg, 0.25mL, 1.6087 mmol). The mixture of activated acids was then transferred to the 1, 8-diazabicyclo [5.4.0 ] ring by pipette]Undec-7-ene solution the resulting mixture was stirred at room temperature for 14h, then the mixture was concentrated, taken up in ethyl acetate (about 30mL) and washed with hydrochloric acid the organic fraction was dried (sodium sulfate), filtered and concentrated purification by silica gel chromatography using a gradient of 25% to 80% ethyl acetate/hexanes to give (4S) -4- [3- [ [6- [ [6- [3- [2- [ tert-butyl (dimethyl) silanyl ] 6- [3- [2 ] tert-butyl (dimethyl) silanyl ] silane as an oil ]Oxy-2-dispiro [2.0.2.1]Hept-7-yl-ethoxy]Pyrazol-1-yl]-2-chloro-pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-tert-butyl 2, 2-bis-methyl-pyrrolidine-1-carboxylate (500mg, 35%). ESI-MS M/z calculated 883.3889, Experimental 884.8(M +1)⁺(ii) a Retention time: 5.39min (LC method P).

And 7: 6- [3- [2- [ tert-butyl (dimethyl) silyl ] oxy-2-dispiro [2.0.2.1] hept-7-yl-ethoxy ] pyrazol-1-yl ] -2-chloro-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] propylamino ] -2-pyridyl ] sulfonyl ] pyridine-3-carboxamide

Reacting (4S) -4- [3- [ [6- [ [6- [3- [2- [ tert-butyl (dimethyl) silyl) group]Oxy-2-dispiro [2.0.2.1]Hept-7-yl-ethoxy]Pyrazol-1-yl]-2-chloro-pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (500mg, 0.5370mmol) was dissolved in dichloromethane (15mL) and cooled in an ice-water bath. Triethylamine (232.32mg, 0.3200mL, 2.2500mmol) was added followed by TBDMSOTf (1.1510g, 1.0000mL, 4.2672mmol) dropwise. The mixture was then stirred at room temperature for 15 h, and was then diluted with dichloromethane (ca. 20mL) and quenched with saturated aqueous sodium bicarbonate solution (20 mL.) the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated the residue was purified by silica gel chromatography using a 0% to 5% methanol/dichloromethane gradient to give 6- [3- [2- [ tert-butyl (dimethyl) silanyl ] silane ]Oxy-2-dispiro [2.0.2.1]Hept-7-yl-ethoxy]Pyrazol-1-yl]-2-chloro-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] methyl]Propylamino group]-2-pyridyl]Sulfonyl radical]Pyridine-3-carboxamide (310mg, 70%). ESI-MS M/z calculated 783.3365, Experimental 785.0(M +1)⁺(ii) a Retention time: 3.29min (LC method P).

And 8: (14S) -8- (3- {2- [ (tert-butyldimethylsilyl) oxy ] oxy]2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy } -1H-pyrazol-1-yl) -12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione

Reacting 6- [3- [2- [ tert-butyl (dimethyl) silyl]Oxy-2-dispiro [2.0.2.1]Hept-7-yl-ethoxy]Pyrazol-1-yl]-2-chloro-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] methyl]Propylamino group]-2-pyridyl]Sulfonyl radical]Pyridine-3-carboxamide (310mg, 0.3952mmol) was dissolved in dimethyl sulfoxide (40 mL). Potassium carbonate (329 mg, 2.3805mmol) was added followed by molecular sieves (0.3952 mmol). The mixture was degassed and protected under a nitrogen balloon and then heated in an oil bath at 140 ℃ for 12 h. After cooling to room temperature, the mixture was diluted with brine (20 mL) and extracted with dichloromethane (2X 20 mL). The solvent was removed and the residue was purified by passing through a short pad of silica gel eluting with ethyl acetate to give (14S) -8- (3- {2- [ (tert-butyldimethylsilyl) oxy ]-2- { dispiro [2.0.2.1]Hept-7-yl } ethoxy } -1H-pyrazol-1-yl) -12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (170mg, 55%).¹H NMR (250MHz, chloroform-d) 8.20(d, J ═ 2.8Hz, 1H), 8.08(d, J ═ 8.4Hz, 1H), 7.67-7.42(m, 2H), 7.33-7.19(s, 1H), 6.57(d, J ═ 7.7Hz, 1H), 5.90(d, 1H), 4.69(s, 1H), 4.17(d, J ═ 5.4Hz, 2H), 4.02-3.73(m, 2H), 3.54-2.88 (m, 3H), 2.61(m, 1H), 2.05(m, 1H), 1.77-1.40(m, 8H), 1.26(s, 6H), 1.11-0.45 (m, 17H), 0.08(2s, 6H). ESI-MS M/z calculated 747.3598, Experimental 748.8(M +1)⁺(ii) a Retention time: 4.9min (LC method P).

And step 9: (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } -2-hydroxyethoxy) -1H-pyrazol-1-yl radical]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 257)

Reacting (14S) -8- (3- {2- [ (tert-butyldimethylsilyl) oxy group]-2- { dispiro [2.0.2.1]Hept-7-yl } ethoxy } -1H-pyrazol-1-yl) -12, 12-dimethyl-2 lambda ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (170mg, 0.2273 mmol) was dissolved in tetrahydrofuran (5mL) in a plastic bottle and cooled in an ice-water bath 70% w/w hydrogen fluoride-pyridine (0.5mL) was added, the mixture was stirred at room temperature for 10min and cooled again in an ice-water bath, another portion of 70% w/w hydrogen fluoride-pyridine (about 0.5mL) was added and the mixture was stirred for 10min with the ice-water bath removed. A third portion of 70% w/w hydrogen fluoride pyridine (about 0.5mL) was added and the mixture was stirred for 10min. Some white precipitate was found towards the end of the solvent removal. The residue was treated with a mixture of ethyl acetate and water (30mL each) and allowed to standStanding at room temperature for about 2 h. The layers were separated and the organic layer was concentrated and the residue was purified by silica gel chromatography using a 0% to 5% methanol/dichloromethane gradient to give (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } -2-hydroxyethoxy) -1H-pyrazol-1-yl radical]-12, 12-dimethyl-2 lambda ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 257) (63mg, 44%).¹H NMR(250 MHz，CDCl₃)8.20(d, J ═ 2.8Hz, 1H), 8.03(d, J ═ 8.2Hz, 1H), 7.65-7.36(m, 2H), 7.18(d, J ═ 8.3Hz, 1H), 6.55(d, J ═ 8.0Hz, 1H), 5.94(d, J ═ 2.8Hz, 1H), 4.71 (s, 1H), 4.38-4.03(m, 3H), 4.03-3.70(m, 2H), 3.33(t, J ═ 8.8Hz, 1H), 3.25-2.89 (m, 2H), 2.56(s, 2H), 2.05(s, 2H), 1.62(m, 6H), overlap with the water peak, 1.38-1.16(m, 4H), 1.08 (m, 6H), 1.04 (d, 1.76H), 1.5H (d, 8.5H), 1H), 1.5H, 5(d, 8.6H). ESI-MS M/z calculated 633.2733, Experimental 634.4(M +1)⁺(ii) a Retention time: 2.87min (LC method R).

Example 84: preparation of (14S) -8- (3- { 2-hydroxy-3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) -12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5(10), 6, 8, 19(23), 20-hexaen-2, 2, 4-trione (compound 259)

Step 1: dimethyl ({ 2-oxo-3- [1- (trifluoromethyl) cyclopropyl)]Propylene }) -lambda ⁶Sulfanones (sulfanones)

Adding 2- [1- (trifluoromethyl) cyclopropyl group into a reaction vessel]Acetic acid (3.0g, 17.85mmol) and dissolved in dichloromethane (30 mL.) the mixture was cooled to 0 deg.C and N, N-dimethylformamide was added(50. mu.L, 0.6457 mmol) and oxalyl chloride (1.9mL, 21.78 mmol.) the resulting reaction was initially stirred at 0 ℃ for 2h, allowed to warm to room temperature over this period of time, then the volatiles were removed by rotary evaporation (vacuum set to 100mbar and water bath at 20 ℃) to afford the desired pure acid chloride. In a separate vessel, trimethylsulfoxonium iodide (12.2g, 55.44mmol) was added and dissolved in tetrahydrofuran (30mL), potassium tert-butoxide (6.2g, 55.25mmol) was added as a 1M solution in tetrahydrofuran, and the resulting mixture was heated to reflux for 2 h. The mixture was cooled to 0 ℃ and the acid chloride prepared above was added as a solution in tetrahydrofuran (30mL), maintaining the temperature below 5 ℃. The mixture was stirred at 0 ℃ for 1 h. Celite was added to the mixture, followed by filtration through celite (the solid was washed with ethyl acetate and the volatiles were concentrated by rotary evaporation). The resulting mixture was washed with water into a separatory funnel and extracted with ethyl acetate (2X 100 mL.) the combined ethyl acetate layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give dimethyl ({ 2-oxo-3- [1- (trifluoromethyl) cyclopropyl) as an oil ]Propylene }) -lambda⁶Thianone (1.9g, 44%).¹H NMR (400MHz, chloroform-d) 3.39(s, 6H), 2.99(s, 1H), 2.40(s, 2H), 1.01(d, J ═ 2.0Hz, 2H), 0.94-0.81(m, 2H). ESI-MS M/z calculated 242.05884, Experimental 243.2(M +1)⁺(ii) a Retention time: 0.72min (LC method E).

Step 2: 1-chloro-3- [1- (trifluoromethyl) cyclopropyl ] propan-2-one

To a 100mL round bottom flask was added dimethyl ({ 2-oxo-3- [1- (trifluoromethyl) cyclopropyl) dissolved in anhydrous tetrahydrofuran (16.0mL) under nitrogen]Propylene }) -lambda⁶-sulfanone (1.9g, 7.843mmol) and then hydrochloric acid (4M in dioxane) (2.5mL, 4M, 10.00mmol) was added, the resulting mixture was heated to 60 ℃ and stirred for 3h, the solvent was evaporated in vacuo (water bath at 130mbar and 20 ℃) and the resulting residue was partitionedBetween ethyl acetate and water, some brine was then added, and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo (water bath 100mbar and 30 ℃) to give 1-chloro-3- [1- (trifluoromethyl) cyclopropyl ] as an orange oil]Propan-2-one (1.57g, 100%).¹H NMR (400MHz, chloroform-d) 3.70(s, 2H), 2.04(s, 2H), 1.17-1.05(m, 2H), 0.85(tt, J ═ 3.8, 2.8, 2.2Hz, 2H).

And step 3: 3- [ 2-oxo-3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazole-1-carboxylic acid tert-butyl ester

To a 100mL flask purged with nitrogen were added tert-butyl 3-hydroxypyrazole-1-carboxylate (1.20g, 6.515mmol), potassium carbonate (1.81g, 13.10mmol) and sodium iodide (11mg, 0.07339mmol) dissolved in N, N-dimethylformamide (15 mL). The mixture was stirred for 5min, and then 1-chloro-3- [1- (trifluoromethyl) cyclopropyl ] was added as a solution in N, N-dimethylformamide (10mL)]Propan-2-one (1.57g, 7.827 mmol). The resulting mixture was heated to 65 ℃ for 16 h. The reaction mixture was poured into saturated brine solution the material was extracted with ethyl acetate (2X 150mL), the organic layers were combined, washed with water (2X 150mL), dried over sodium sulfate, filtered and concentrated the orange residue was purified by silica gel chromatography using a gradient of 100% hexane to 60% ethyl acetate/hexane to give 3- [ 2-oxo-3- [1- (trifluoromethyl) cyclopropyl ] as a pale yellow oil]Propoxy group]Pyrazole-1-carboxylic acid tert-butyl ester (700mg, 31%).¹H NMR (400MHz, chloroform-d) 7.86(d, J ═ 2.8Hz, 1H), 5.96(d, J ═ 2.8Hz, 1H), 4.93(s, 2H), 2.77(s, 2H), 1.60(s, 9H), 1.15-1.07(m, 2H), 0.91-0.86(m, 2H). ESI-MS M/z calculated 348.1297, Experimental 349.2(M +1) ⁺(ii) a Retention time: 1.73min (LC method E).

And 4, step 4: 1- (1H-pyrazol-3-yloxy) -3- [1- (trifluoromethyl) cyclopropyl ] propan-2-one

To 3- [ 2-oxo-3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]To a solution of pyrazole-1-carboxylic acid tert-butyl ester (700mg, 2.010mmol) in dichloromethane (14mL) was added trifluoroacetic acid (3.1mL, 40.24mmol) and the mixture was stirred for 1h the solvent was removed and the resulting oil was evaporated and dried in vacuo to give a light yellow solid. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 1- (1H-pyrazol-3-yloxy) -3- [1- (trifluoromethyl) cyclopropyl]Propan-2-one (498mg, 100%). ESI-MS M/z calculated 248.07726, Experimental 249.2(M +1)⁺(ii) a Retention time: 1.11min (LC method E).

And 5: 2-chloro-6- [3- [ 2-oxo-3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carboxylic acid tert-butyl ester

2, 6-dichloropyridine-3-carboxylic acid tert-butyl ester (497mg, 2.003mmol), 1- (1H-pyrazol-3-yloxy) -3- [1- (trifluoromethyl) cyclopropyl]Propan-2-one (498mg, 2.006mmol) and potassium carbonate (625mg, 4.522 mmol) were combined in anhydrous dimethylsulfoxide (14 mL.) 1, 4-diazabicyclo [2.2.2 ] was added ]Octane (45mg, 0.4012mmol) and the mixture stirred at room temperature under nitrogen for 16 h. The reaction mixture was diluted with water (16mL) and stirred for 15 min. The resulting mixture was diluted with ethyl acetate and washed with water (3X 50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure the orange residue was purified by silica gel chromatography using a gradient of 100% hexane to 60% ethyl acetate/hexane to give a light yellow oil which was then dried in vacuo to give 2-chloro-6- [3- [ 2-oxo-3- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (500mg, 54%).¹H NMR (400MHz, chloroform-d) 8.38(d, J ═ 2.8Hz, 1H), 8.18(d, J ═ 8.4Hz, 1H), 7.59(d, J ═ 8.4Hz, 1H), 6.04(d, J ═ 2.8Hz, 1H), andH) 4.87 (s, 2H), 2.79(s, 2H), 1.62(s, 10H), 1.14-1.09(m, 2H), 0.85(dd, J ═ 3.0, 1.7Hz, 2H). ESI-MS M/z calculated 459.11728, Experimental 460.2(M +1)⁺(ii) a Retention time: 2.21min (LC method E).

Step 6: 2-chloro-6- [3- [ 2-oxo-3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carboxylic acid

2-chloro-6- [3- [ 2-oxo-3- [1- (trifluoromethyl) cyclopropyl]Propoxy group ]Pyrazol-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (500mg, 1.087mmol) was dissolved in dichloromethane (11mL) and cooled to 0 ℃ in an ice bath. Hydrochloric acid (1.5mL, 4M in dioxane, 6.000mmol) was slowly added to the mixture, and the mixture was stirred at 0 ℃ for 1 h. Hydrochloric acid (5.5mL, 4M in dioxane, 22.00mmol) was additionally added and stirred at 0 ℃ for 30min, followed by stirring at room temperature for 2 h-hydrochloric acid (5.435mL, 4M in dioxane, 21.74mmol) was additionally added and stirred at room temperature for over 17 h. The reaction mixture was concentrated under reduced pressure to a white solid, which was then slurried in diethyl ether, filtered and slurried again in diethyl ether. The solid was collected by vacuum filtration and dried in vacuo for 20h to provide 2-chloro-6- [3- [ 2-oxo-3- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxylic acid (237.5mg, 54%). ESI-MS M/z calculated 403.05466, Experimental 404.2(M +1)⁺(ii) a Retention time: 1.59min (LC method E).

And 7: (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [ 2-oxo-3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- [ 2-oxo-3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxylic acid (166mg, 0.4112 mmol)) And carbonyldiimidazole (75mg, 0.4625mmol) were combined in tetrahydrofuran (4.0 mL) and stirred at room temperature for 110min, then (4S) -2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (187mg, 0.4533mmol) followed by addition of anhydrous 1, 8-diazabicyclo [5.4.0]Undec-7-ene (160 μ L, 1.070mmmol), and the reaction was stirred at room temperature for 20 h. the reaction was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate followed by brine the organic layer was dried over sodium sulfate, filtered, evaporated and then purified by silica gel chromatography using a gradient of 100% hexane to 100% ethyl acetate followed by a second silica gel column using a gradient of 100% dichloromethane to 15% methanol/dichloromethane to give (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [ 2-oxo-3- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Propoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (173.7mg, 53%). ESI-MS M/z calculated 797.25854, experimental 798.2(M +1) ⁺(ii) a Retention time: 2.21min (LC method E).

And 8: (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [ 2-hydroxy-3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [ 2-oxo-3- [1- (trifluoromethyl) cyclopropyl ] under nitrogen]Propoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (80mg, 0.1002mmol) to a stirred solution in methanol (1.25mL) was added sodium borohydride (10mg, 0.2643mmol) portionwise to control significant foaming after addition took 1min to complete the reaction was a solution. The reaction was concentrated by rotary evaporation and then diluted with ethyl acetate and washed with water (2 × 20mL) followed by brine (1 ×). The organic layer was then separated, dried over sodium sulfate, filtered andand (5) concentrating. The residue was dried in vacuo to give (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [ 2-hydroxy-3- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Propoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (80mg, 100%). ESI-MS calculated M/z 799.2742, Experimental 800.3(M +1) ⁺(ii) a Retention time: 2.15min (LC method E).

And step 9: (14S) -8- (3- { 2-hydroxy-3- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Propoxy } -1H-pyrazol-1-yl) -12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5(10), 6, 8, 19(23), 20-hexaen-2, 2, 4-trione (compound 259)

To a solution containing (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [ 2-hydroxy-3- [1- (trifluoromethyl) cyclopropyl ] group]Propoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]To a flask of-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (80mg, 0.09996mmol) was added dichloromethane (2.5mL) and hydrochloric acid (500 μ L, 4M in dioxane, 2.000 mmol). After stirring for 90min, the mixture was evaporated to dryness, then diluted with ether (5mL) and reconcentrated by rotary evaporation the residue was subsequently diluted with ether (5mL) and reconcentrated by rotary evaporation the residue was dried in vacuo overnight, and then mixed with potassium carbonate (139mg, 1.006mmol),

Molecular sieves and dimethylsulfoxide (3.5mL) were combined in a vial, purged with nitrogen, capped, heated to 155 ℃ and stirred for 4h, cooled to room temperature, and the mixture was filtered, diluted with ethyl acetate and washed with water (2 x 20mL), then brine. The residue was purified by silica gel chromatography using a gradient of 100% hexane to 100% ethyl acetate to give (14S) -8- (3- { 2-hydroxy-3- [1- (trifluoromethyl) cyclopropyl) as an off-white solid ]Propoxy } -1H-pyrazol-1-yl) -12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5(10), 6, 8, 19(23), 20-hexaen-2, 2, 4-trione (compound 259) (27.91mg, 42%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.49(s, 1H), 8.22(d, J ═ 2.8Hz, 1H), 7.82(d, J ═ 8.3Hz, 1H), 7.58(dd, J ═ 8.5, 7.2Hz, 1H), 7.05(d, J ═ 7.2Hz, 1H), 6.99(s, 1H), 6.92(d, J ═ 8.2Hz, 1H), 6.71(d, J ═ 8.5Hz, 1H), 6.13(d, J ═ 2.8Hz, 1H), 5.03(s, 1H), 4.10(dd, J ═ 4.9, 2.4Hz, 2H), 3.97(d, J ═ 4.7Hz, 2H), 3.16(s, 1H), 2.95(d, J ═ 4.9, 2.4Hz, 2H), 3.6.7H, 1H), 3.95 (d, J ═ 4, 1H), 1H), 1.65 (dd, 13, 1H), 1H, 6.6.7 (dd, 13, 1H), 6.7 (d, 13, 1H), 6.7H), 3H) 1.57(d, J ═ 12.4Hz, 2H), 1.52(s, 3H), 1.37-1.27(M, 1H), 1.01-0.90(M, 2H), 0.90-0.78 (M, 2H), ESI-MS M/z calculated 663.24506, experimental 664.4(M +1)⁺(ii) a Retention time: 1.88min (LC method E).

Example 85: preparation of (14S) -8- [3- (2- { dispiro [ [2.0.2.1 ] ]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-22-hydroxy-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound (260)

Step 1: 2-bromo-6-nitro-pyridin-3-ol

To a solution of 2-bromopyridin-3-ol (46g, 264.38mmol) in sulfuric acid (230mL) was added nitric acid (24.989g, 17.685mL, 277.60mmol) (70%) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 30min, then at room temperature for 48h, then poured into cold water (200 mL)) And extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with water (150mL) and brine (150mL), dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by chromatography (silica gel, 0% to 20% ethyl acetate/heptane) to give 2-bromo-6-nitro-pyridin-3-ol as a yellow solid (9.2g, 16%).¹H NMR(300MHz，CDCl₃) 8.24(d, J ═ 8.5Hz, 1H), 7.54(d, J ═ 8.5Hz, 1H), 6.37(br.s., 1H), ESI-MS M/z calculated 217.9327, experimental 221.0(M +1)⁺(ii) a Retention time: 1.492min (LC method N).

Step 2: 3-benzyloxy-2-bromo-6-nitro-pyridine

To a solution of sodium hydride (2g, 50.005mmol) in dimethylformamide (30mL) at 0 ℃ was added a solution of 2-bromo-6-nitro-pyridin-3-ol (9g, 41.097mmol) in dimethylformamide (60mL) dropwise after 30min benzyl bromide (7.4776g, 5.2mL, 43.720mmol) was added, the cold bath was removed, and the reaction was stirred at room temperature for 16 h. The crude mixture was diluted with water (75mL) and extracted with ethyl acetate (3X 75 mL). The combined organic layers were washed with water (2 × 75mL), brine (100mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The solid residue was triturated in a mixture of ethyl acetate/heptane (9/1) (50mL), then filtered and washed with additional ethyl acetate/heptane (9/1) (50mL) to give 3-benzyloxy-2-bromo-6-nitro-pyridine (8.7g, 68%) as a yellow solid. ¹H NMR (300MHz, dimethylsulfoxide-d)₆)8.42(d, J ═ 8.5Hz, 1H), 7.90(d, J ═ 8.8Hz, 1H), 7.30-7.59(m, 5H), 5.43(s, 2H). ESI-MS M/z calculated 307.9797, Experimental 311.0(M +1)⁺(ii) a Retention time: 1.956min (LC method S).

And step 3: 3- [ (3-benzyloxy-6-nitro-2-pyridyl) sulfanyl ] propionic acid 2-ethylhexyl ester

To a mixture of 3-benzyloxy-2-bromo-6-nitro-pyridine (14.5g, 46.908mmol), Xantphos (1.7g, 2.9380 mmol), Pd₂(dba)₃(1.35g, 1.4743mmol) in toluene (300mL) 2-ethylhexyl 3-sulfanylpropionate (11.5g, 52.666mmol) was added followed by N, N-diisopropylethylamine (12.614g, 17mL, 97.599mmol). The resulting solution was evacuated and backfilled with nitrogen three times, and then refluxed at 110 deg.C overnight after cooling to room temperature, the reaction was filtered through a pad of celite and washed with ethyl acetate (75 mL). The combined filtrates were concentrated and the resulting residue was purified by silica gel chromatography (gradient of 0% to 15% ethyl acetate/heptane) to give 2-ethylhexyl 3- [ (3-benzyloxy-6-nitro-2-pyridinyl) sulfanyl) propionate (20g, 95%).¹H NMR(300MHz，CDCl₃)7.94(d, J ═ 8.5Hz, 1H), 7.32-7.51(M, 5H), 7.09-7.17(M, 1H), 5.25(s, 2H), 3.97-4.12(M, 2H), 3.51(t, J ═ 6.9Hz, 2H), 2.89(t, J ═ 6.8Hz, 2H), 1.51-1.67(M, 1H), 1.20-1.43(M, 8H), 0.81-0.96(M, 6H), ESI-MS M/z calculated value 446.1875, experimental value 447.2(M +1) ⁺(ii) a Retention time: 4.181min (LC method T).

And 4, step 4: 3- [ (3-benzyloxy-6-nitro-2-pyridyl) sulfonyl ] propionic acid 2-ethylhexyl ester

To 3- [ (3-benzyloxy-6-nitro-2-pyridyl) sulfanyl group at room temperature]To a solution of 2-ethylhexyl propionate (20g, 44.787mmol) in dichloromethane (400mL) was added slowly m-chloroperbenzoic acid (21g, 77% w/w in tetrahydrofuran, 93.703 mmol.) the mixture was stirred at this temperature overnight the solid was filtered off and the mixture was washed with 10% sodium thiosulfate solution (150mL), 5% sodium bicarbonate solution (2 x 100mL), water (100mL) and brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3- [ (3-benzyloxy-6-nitro-2-pyridinyl) sulfonyl as a yellow solid]2-ethylhexyl propionate (20.5 g, 96%).¹H NMR(300MHz，CDCl₃)8.39(d，J＝9.1Hz，1H)，7.64(d，J＝9.1Hz， 1H)，7.31-7.52(m，5H)，5.45(s，2H)，4.03(dd，J＝5.7，2.5Hz，2H)，3.89-4.00(m，2H)， 3.04(t，J＝7.5Hz，2H)，1.50-1.66(m，1H)，1.22-1.41(m，8H)，0.83-0.95(m，6H)。

And 5: 3- [ (6-amino-3-benzyloxy-2-pyridyl) sulfonyl ] propionic acid 2-ethylhexyl ester

To 3- [ (3-benzyloxy-6-nitro-2-pyridyl) sulfonyl group]To a solution of 2-ethylhexyl propionate (5g, 10.448mmol) in ethanol (280mL) and water (80mL) were added iron (2.4g, 42.976mmol) and ammonium chloride (1.7 g, 31.781 mmol.) the reaction was stirred at 100 ℃ for 1.5h and the dark solution was cooled to room temperature, filtered through celite and washed with dichloromethane (150 mL). The filtrate was concentrated under reduced pressure the crude product was diluted in water (100mL) and extracted with dichloromethane (2X 75 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure the resulting crude product was purified by trituration in t-butyl methyl ether (50mL), the suspension was filtered and washed with t-butyl methyl ether (50mL), the resulting off-white solid was dried under vacuum overnight to provide 3- [ (6-amino-3-benzyloxy-2-pyridinyl) sulfonyl ] amide ]2-ethylhexyl propionate (4.5g, 96%). ESI-MS M/z calculated 448.2032, Experimental 449.2(M +1)⁺(ii) a Retention time: 2.35min (LC method I).

Step 6: 3- [ (3-benzyloxy-6-fluoro-2-pyridinyl) sulfonyl ] propionic acid 2-ethylhexyl ester

Reacting 3- [ (6-amino-3-benzyloxy-2-pyridyl) sulfonyl group]A solution of 2-ethylhexyl propionate (4.5g, 10.032mmol) in pyridine hydrogen fluoride (55.0g, 50mL, 554.96mmol) was cooled to-52 ℃. The resulting red solution was treated with sodium nitrite (1.4g, 20.291mmol) and allowed to warm to room temperatureStir at room temperature overnight and pour slowly over ice and water (50 mL.) the mixture is neutralized by careful addition of aqueous sodium bicarbonate solution and extracted with ethyl acetate (3 × 50 mL.) the combined organic layers are dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide crude 3- [ (3-benzyloxy-6-fluoro-2-pyridinyl) sulfonyl]2-ethylhexyl propionate (4g, 88%). ESI-MS M/z calculated 451.1829, Experimental 452.2(M +1)⁺(ii) a Retention time: 2.46min (LC method I).

And 7: 3-benzyloxy-6-fluoro-pyridine-2-sulfonamide

To 3- [ (3-benzyloxy-6-fluoro-2-pyridyl) sulfonyl group ]To a solution of 2-ethylhexyl propionate (8g, 17.717mmol) in dimethyl sulfoxide (48mL) was added 1, 8-diazabicyclo (5.4.0) undec-7-ene (5.5550g, 5.5 mL, 36.489 mmol). The reaction was stirred at room temperature for 1h and a solution of hydroxylamine-O-sulfonic acid (10.1g, 89.307 mmol) and sodium acetate (6g, 73.141mmol) in water (32mL) was added the reaction stirred at room temperature for 1h, diluted with water (100mL) and extracted with ethyl acetate (3 x 75mL), the combined organic layers were washed with brine (30mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure the crude product was purified by silica gel flash chromatography (gradient of 10% to 40% ethyl acetate/heptane) to give 3-benzyloxy-6-fluoro-pyridine-2-sulfonamide as an off-white solid (4.1g, 82%).¹H NMR (300MHz, dimethylsulfoxide-d)₆)5.38(s，2H)，7.25-7.48 (m，4H)，7.49-7.57(m，4H)，7.96(dd，J＝9.0，6.0Hz，1H)；¹⁹F NMR (282MHz, dimethyl sulfoxide-d)₆) Calculated values of-78.5-78.2 (M, 1F). ESI-MS M/z 282.0474, Experimental value 283.1(M +1)⁺(ii) a Retention time: 2.14min (LC method H).

And 8: (4S) -4- [3- [ (5-benzyloxy-6-sulfamoyl-2-pyridyl) amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

A20 mL vial was charged with (4S) -4- (3-aminopropyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (291mg, 1.135mmol), 3-benzyloxy-6-fluoro-pyridine-2-sulfonamide (321mg, 1.137 mmol), anhydrous dimethylsulfoxide (3mL), and N, N-diisopropylethylamine (0.3mL, 1.722mmol) under nitrogen. The vial was capped and stirred at 85 ℃ for 3h, then at 110 ℃ for 16h, then at 120 ℃ for 29 h. The mixture was diluted with ethyl acetate (50mL), water (50mL) and 10% citric acid (10 mL). The two phases were separated. The organic phase was washed with brine (30mL), dried over sodium sulfate, and the solvent was evaporated the product was purified by flash chromatography on silica gel using a gradient of ethyl acetate/hexane (0% to 60% over 30min) to give (4S) -4- [3- [ (5-benzyloxy-6-sulfamoyl-2-pyridyl) amino as a foamy solid ]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (342mg, 58% yield, 92% purity).¹H NMR (400MHz, dimethylsulfoxide-d)₆) 7.54-7.47 (M, 2H), 7.44(d, J ═ 9.0Hz, 1H), 7.41-7.33(M, 2H), 7.33-7.22(M, 1H), 6.94 (s, 2H), 6.60(d, J ═ 8.9Hz, 1H), 6.49(t, J ═ 5.5Hz, 1H), 5.11(s, 2H), 3.55(q, J ═ 8.7 Hz, 1H), 3.27-3.16(M, 2H), 2.79(q, J ═ 10.1Hz, 1H), 2.10 (width s, 1H), 1.93-1.85(M, 1H), 1.54-1.43(M, 2H), 1.43-1.37(M, 15H), 1.24(s, 3H), 1.93-1.519 (M, 519, 25M/M + 1H), experimental calculated values (M, 1 z + 1M, 1H)⁺(ii) a Retention time: 1.88min (LC method B).

And step 9: (4S) -4- [3- [ [ 5-benzyloxy-6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1] hept-7-ylethoxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

A20 mL vial was charged with 2-chloro-6- [3- (2-dispiro [2.0.2.1] under nitrogen]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (100mg, 0.2779mmol) and anhydrous tetrahydrofuran (2 mL). Carbonyldiimidazole (45mg, 0.2775mmol) was added and mixed with stirring at room temperature under nitrogenThing 4 h. A second amount of carbonyldiimidazole (45mg, 0.2775mmol) was added and the mixture was stirred at room temperature for 3 h. Preparation of (4S) -4- [3- [ (5-benzyloxy-6-sulfamoyl-2-pyridyl) amino group in a separate 20mL flask under a nitrogen atmosphere ]Propyl radical]-a solution of tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (121mg, 0.2333mmol) in anhydrous tetrahydrofuran (1mL) and subsequently added to the activated ester solution by syringe. Addition of 1, 8-diazabicyclo [5.4.0 ] via syringe]Undec-7-ene (0.18mL, 1.204mmol) and the reaction mixture stirred at room temperature under a nitrogen atmosphere after 17h, the solvent was removed under reduced pressure and the resulting thick oil was treated with ethyl acetate (25mL) and water (25 mL). Aqueous hydrochloric acid (250 μ L, 6M, 1.500mmol) was slowly added (final pH 5) and the two phases were separated. The aqueous phase was extracted with ethyl acetate (30 mL). The combined organic extracts were washed with brine (30mL) and dried over sodium sulfate. After filtration and evaporation of the solvent, the residue was dissolved in dichloromethane and purified by flash chromatography on silica gel using a gradient of ethyl acetate/hexane (0% to 100% over 30min) to give (4S) -4- [3- [ [ 5-benzyloxy-6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1 ] as a colourless membrane]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (99mg, 49% yield, 93% purity). ESI-MS M/z calculated 859.34937, Experimental 860.5 (M +1) ⁺(ii) a Retention time: 1.82min (LC method B).

Step 10: n- [ [ 3-benzyloxy-6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] propylamino ] -2-pyridinyl ] sulfonyl ] -2-chloro-6- [3- (2-dispiro [2.0.2.1] hept-7-ylethoxy) pyrazol-1-yl ] pyridine-3-carboxamide (trifluoroacetate)

To (4S) -4- [3- [ [ 5-benzyloxy-6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (99mg, 0.1151mmol) in dichloromethane (0.5mL) and toluene (0.2mL)Trifluoroacetic acid (100 μ L, 1.298mmol) was added to the solution and the mixture was stirred at ambient temperature for 23h the solvent was removed in vacuo at a bath temperature set at 40 ℃ to give a thick yellow oil. The oil was diluted with toluene (5mL) and the solvent removed in vacuo at 40 ℃ to give N- [ [ 3-benzyloxy-6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] as a yellow resin]Propylamino group]-2-pyridyl]Sulfonyl radical]-2-chloro-6- [3- (2-dispiro [2.0.2.1]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carboxamide (trifluoroacetate) (100mg, 99%). ESI-MS M/z calculated 759.29694, Experimental 760.4(M +1)⁺(ii) a Retention time: 1.9min (LC method B).

Step 11: (14S) -22- (benzyloxy) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione

To N- [ [ 3-benzyloxy-6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl group]Propylamino group]-2-pyridyl]Sulfonyl radical]-2-chloro-6- [3- (2-dispiro [2.0.2.1 ]]Hept-7-ylethoxy) pyrazol-1-yl]To a solution of pyridine-3-carboxamide (trifluoroacetate) (100mg, 0.1144mmol) in NMP (2mL) was added potassium carbonate (180mg, 1.302 mmol.) the mixture was purged with nitrogen for 5 min. The mixture was heated at 150 ℃ for 20 h. The reaction mixture was cooled to room temperature and added to water (8 mL). The mixture was carefully acidified with aqueous hydrochloric acid (500 μ L, 6M, 3.000mmol) until pH 1 to give a multivesicular slurry. The solid was collected on paper by filtration. The wet solid was dissolved in ethyl acetate and the solution was dried over sodium sulfate, followed by filtration the solvent was removed and the residue was purified by flash chromatography on silica gel using a gradient of methanol/dichloromethane (0% to 5% over 30min) to give (14S) -22- (benzyloxy) -8- [3- (2- { dispiro [2.0.2.1 ] as an off-white solid ]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111,14.05，10]tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (31mg, 37%). ESI-MS M/z calculated 723.3203, experimental 724.5(M +1)⁺(ii) a Retention time: 2.19min (LC method B).

Step 12: (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-22-hydroxy-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 260)

A100 mL flask was charged with (14S) -22- (benzyloxy) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (31mg, 0.04282mmol) and methanol (6 mL). The solution was sparged with nitrogen. 10% palladium on carbon (moist, Degussa, 21mg, 0.01973mmol) was added and the mixture was stirred under an atmosphere of hydrogen (balloon) for 3h the solution was sparged with nitrogen, diluted with methanol and filtered through celite. After evaporation of the solvent, the residue was dissolved in dimethyl sulfoxide (1 mL), the solution was microfiltered and prepared by reverse phase preparative HPLC (C) ₁₈) Purification using an acetonitrile/water gradient (30% to 99% over 15min, 950 μ L injection without modifier.) the pure fractions were collected and the solvent was removed by evaporation, the residue was treated with dichloromethane/hexanes and the solvent was evaporated to give (14S) -8- [3- (2- { dispiro [2.0.2.1 ] as an off-white solid]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-22-hydroxy-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 260) (10mg, 36%).¹H NMR (400 MHz, dimethylsulfoxide-d)₆)12.39(br s, 1H), 9.07(br s, 1H, alternative), 8.21(d, J ═ 2.8Hz, 1H), 7.80(br d, J ═ 8.0Hz, 1H), 7.20(br s, 1H), and combinations thereof) 6.91(br d, J ═ 8.2Hz, 1H), 6.69(br d, J ═ 8.8Hz, 1H), 6.28(brs, 1H, alternative), 6.08(d, J ═ 2.6Hz, 1H), 4.21(t, J ═ 6.7Hz, 2H), 3.77 (brs, 1H), 3.20(brs, 1H), 2.96-2.79(M, 2H), 2.12(brs, 1H), 1.91-1.50 (M, 13H), 1.47(t, J ═ 6.5Hz, 1H), 1.42-1.29(M, 1H), 0.89-0.78(M, 4H), 0.68-0.60 (M, 2H), 0.53-0.44(M, 2H), MS-ESI/M, 633.2733 + 634.3 (calculated value of M + z) ⁺(ii) a Retention time: 2.39min (LC method B).

Example 86: preparation of (14S) -22-hydroxy-12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 261)

Step 1: (S) -4- [3- [ [ 5-benzyloxy-6- [ [ 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

A20 mL vial was charged with 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl under nitrogen]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxylic acid (188mg, 0.4824mmol) and anhydrous tetrahydrofuran (3 mL). Carbonyldiimidazole (75mg, 0.4625mmol) was added and the mixture was stirred at room temperature under nitrogen for 4 h. A second amount of carbonyldiimidazole (75mg, 0.4625mmol) was added and the mixture was stirred at room temperature for 2 h. Preparation of (4S) -4- [3- [ (5-benzyloxy-6-sulfamoyl-2-pyridyl) amino group in a separate 20mL flask under a nitrogen atmosphere]Propyl radical]-a solution of tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (204mg, 0.3933mmol) in anhydrous tetrahydrofuran (2 mL) and then added to the activated ester solution by syringe Injector addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (0.31mL, 2.073mmol) and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 5 days. After removal of the solvent under reduced pressure and treatment of the resulting thick oil with ethyl acetate (50mL) and water (50mL), hydrochloric acid (450 μ L, 6M, 2.700mmol) is slowly added (final pH ═ 5), and the two phases are separated, the aqueous phase is extracted with ethyl acetate (30mL), the combined organic extracts are washed with brine (30mL) and dried over sodium sulfate, after filtration and evaporation of the solvent, the residue is dissolved in dichloromethane and purified by silica gel flash chromatography using a gradient of ethyl acetate/hexane (0% to 100% over 30 min.) the impurities are co-eluted with the product, which are removed by silica gel chromatography under the same conditions as the first column with a second purification 1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (109mg, 31% yield, 86% purity). ESI-MS M/z calculated 889.3211, Experimental 890.4(M +1) ⁺(ii) a Retention time: 2.49 min (LC method B).

Step 2: n- [ [ 3-benzyloxy-6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] propylamino ] -2-pyridinyl ] sulfonyl ] -2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carboxamide (bistrifluoroacetate)

To (4S) -4- [3- [ [ 5-benzyloxy-6- [ [ 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Propoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]To a solution of tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (109mg, 0.1224mmol) in dichloromethane (0.5mL) and toluene (0.2mL) was added trifluoroacetic acid (100 μ L, 1.298mmol) and the mixture was stirred at ambient temperature for 23 h. The solvent was removed under vacuum at a bath temperature set at 40 ℃. The residue was diluted with toluene (5mL) and the solvent was removed in vacuo at a bath temperature set at 40 ℃The residue was treated with dichloromethane/hexane and the solvent was evaporated to give N- [ [ 3-benzyloxy-6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] as an off-white solid]Propylamino group]-2-pyridyl]Sulfonyl radical]-2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxamide (Dichloroacetic acid salt) (130mg, quantitative yield.) ESI-MS M/z calculated 789.2687, Experimental value 790.5(M +1) ⁺(ii) a Retention time: 1.85min (LC method B).

And step 3: (14S) -22- (benzyloxy) -12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Propoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione

To N- [ [ 3-benzyloxy-6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl group]Propylamino group]-2-pyridyl]Sulfonyl radical]-2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]To a solution of pyridine-3-carboxamide (ditrifluoroacetate) (130mg, 0.1277mmol) in NMP (3mL) was added potassium carbonate (230mg, 1.664 mmol.) the mixture was purged with nitrogen for 5 min. The mixture was heated at 150 ℃ for 22 h. The reaction mixture was cooled to room temperature and added to water (10 mL). The mixture was carefully acidified with aqueous hydrochloric acid (500 μ L, 6M, 3.000mmol) until pH 1 to give a multivesicular slurry. The wet solids were dissolved in ethyl acetate and the solution was dried over sodium sulfate and filtered. The solvent was evaporated and the residue was purified by flash chromatography on silica gel using a gradient of methanol/dichloromethane (0% to 5% over 30min) to give (14S) -22- (benzyloxy) -12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl) -as a white solid ]Propoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (38mg, 39%). ESI-MS M/z calculated 753.29205, Experimental 754.5(M +1)⁺(ii) a Health-care productRetention time: 2.38min (LC method B).

And 4, step 4: (14S) -22-hydroxy-12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Propoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 261)

A100 mL flask was charged with (14S) -22- (benzyloxy) -12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (39mg, 0.05174mmol) and methanol (8mL) the solution was sparged with nitrogen 10% palladium on carbon (moist, Degussa, 27mg, 0.02537mmol) was added and the mixture was stirred under an atmosphere of hydrogen (balloon) for 4 h. After evaporation of the solvent, the residue was dissolved in dimethyl sulfoxide (1 mL), the solution was microfiltered and prepared by reverse phase preparative HPLC (C) ₁₈) Purification using a gradient of acetonitrile/water (30% to 99% over 15min, 950 μ L injection without modifier.) the pure fractions were collected and the solvent was removed by evaporation the residue was treated with dichloromethane/hexane and the solvent was evaporated to give (14S) -22-hydroxy-12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl) as an off-white solid]Propoxy } -1H-pyrazol-1-yl]-2λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 261) (22mg, 63%).¹H NMR (400 MHz, dimethylsulfoxide-d)₆)12.38 (width s, 1H), 9.07(br s, 1H), 8.21(d, J ═ 2.7Hz, 1H), 7.79 (br s, 1H), 7.20(br s, 1H), 6.90(br s, 1H), 6.68(br s, 1H), 6.28(br s, 1H), 6.10(br s, 1H), 4.20(t, J ═ 6.2Hz, 2H), 3.76(br s, 1H), 3.21(br s, 1H), 2.98-2.75(m, 2H), 2.12 (br s, 1H), 1.93 (br s, 1H)-1.77(m, 3H), 1.78-1.66(m, 3H), 1.68-1.46(m, 8H), 1.37(br m, 2H), 0.95-0.88(m, 2H), 0.79-0.68(m, 2H). ESI-MS M/z calculated 663.24506, Experimental 664.3(M +1)⁺(ii) a Retention time: 2.24min (LC method B).

Example 87: preparation of 2-imino-12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaene-2, 4-dione (diastereomer pair 1) (Compound 262) and 2-imino-12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaene-2, 4-dione (diastereomer pair 2) (Compound 263)

Step 1: 2, 6-Difluoropyridine-3-carboxylic acid tert-butyl ester

To 2, 6-difluoropyridine-3-carboxylic acid (10g, 62.858mmol) and BF at 0 ℃ over 10min₃·Et₂To a solution of O (0.4 mL, 3.2mmol, 0.05 equiv.) in anhydrous tetrahydrofuran (60mL) was slowly added tert-

butyl

2, 2, 2-trichloroacetate (10g, 45.8 mmol). The reaction solution was stirred at room temperature under nitrogen atmosphere for 2h at room temperature more tert-

butyl

2, 2, 2-trichloroethaniminate (20g, 91.5mmol) and BF were added₃·Et₂O (0.4 mL.) the reaction was stirred for 1h then allowed to stand over the weekend before quenching with saturated aqueous sodium bicarbonate solution, the mixture was extracted with ethyl acetate (2 × 60mL), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purifying the residue by silica gel chromatography using a gradient of 0% to 20% ethyl acetate/heptane to yield Tert-butyl 2, 6-difluoropyridine-3-carboxylate as a white solid (12g, 89%). ESI-MS M/z calculated 215.0758, Experimental 216.1(M +1)⁺(ii) a Retention time: 2.13min (LC method I).

Step 2: 2-fluoro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxylic acid tert-butyl ester

1, 4-diazabicyclo [2.2.2]Octane (125mg, 1.1144mmol) was added to tert-butyl 2, 6-difluoropyridine-3-carboxylate (1.2g, 5.5763mmol) and 3- [2- [1- (trifluoromethyl) cyclopropyl ] ester]Ethoxy radical]-1H-pyrazole (1.29g, 5.8585 mmol). The mixture was stirred for 10min and potassium carbonate (1.2g, 8.6827 mmol) was added. The mixture was stirred at 20 ℃ under nitrogen for 16 h. The reaction mixture was diluted with ethyl acetate (100mL), washed with water (3X 30mL), brine (30mL), dried over sodium sulfate, filtered and evaporated the residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate/heptane (0% -15%) to give 2-fluoro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] propyl as a white solid]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (1.46g, 63% yield).¹H NMR(300MHz，CDCl₃)0.71-0.78(m，2H)，1.01-1.05(m， 2H)，1.60(s，9H)，2.10(t，J＝7.1Hz，2H)，4.41(t，J＝7.1Hz，2H)，5.95(d，J＝2.9Hz， 1H)，7.63(dd，J＝8.2，1.2Hz，1H)，8.29(d，J＝2.8Hz，1H)，8.32-8.38(m，1H).¹⁹F NMR (282MHz，CDCl₃) -69.9(s, 3F), -62.4(d, J ═ 9.2Hz, 1F), ESI-MS M/z calcd 415.1519, experimental 416.2(M +1) ⁺(ii) a Retention time: 2.69min (LC method U).

And step 3: 2-fluoro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxylic acid

Trifluoroacetic acid (3mL) was added to 2-fluoro-6- [3- [2- ], a1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (1.46g, 3.5148mmol) in dichloromethane (12 mL.) the mixture was stirred at 40 ℃ for 4h, then the mixture was concentrated under reduced pressure and dried in vacuo to provide 2-fluoro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (1.26g, 100%).¹H NMR(300MHz，CDCl₃)0.84-.091(m，2H)，0.93-0.99(m，2H)，2.09(t， J＝7.0Hz，2H)，4.35(t，J＝7.0Hz，2H)，6.21(d，J＝2.7Hz，1H)，7.67(d，J＝9.3Hz，1H)， 8.42(d，J＝3.1Hz，1H)，8.50(dd，J＝9.3，8.5Hz，1H)，13.48(br.s.，1H).¹⁹F NMR(282 MHz，CDCl₃) -68.38(s, 3F), -63.25(d, J ═ 9.5Hz, 1F). ESI-MS M/z calculated 359.0893, Experimental 360.1(M +1)⁺(ii) a Retention time: 2.19min (LC method I).

And 4, step 4: 2-fluoro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide

To 2-fluoro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]To a suspension of pyridine-3-carboxylic acid (1.26g, 3.5071mmol) in dichloromethane (20mL) was added one drop of N, N-dimethylformamide (0.015 mL), followed by dropwise addition of oxalyl chloride (625.65mg, 0.43mL, 4.9293 mmol). The reaction was stirred at room temperature for 2h until bubbling ceased. The solvent was removed under reduced pressure the resulting white solid was dissolved in anhydrous tetrahydrofuran (10mL) and added to a mixture of 28% aqueous ammonium hydroxide (10mL) and tetrahydrofuran (5mL) cooled with an ice-water bath. The reaction was then stirred at room temperature for 1h, and then diluted with ethyl acetate (100 mL), washed with water (20mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-fluoro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] as a white solid ]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (1.3 g, quantitative yield).¹H NMR(300MHz，CDCl₃)0.70-0.79(m，2H)，0.99-1.08(m，2H)，2.10(t，J＝7.2Hz，2H)，4.42(t，J＝7.1Hz，2H)，5.80(br.s，1H)，5.97(d，J＝2.9Hz，1H)， 6.61-6.71(m，1H)，7.74(dd，J＝8.3，2.0Hz，1H)，8.28(d，J＝2.8Hz，1H)，8.62(dd， J＝9.8，8.3Hz，1H).¹⁹F NMR(282MHz，CDCl₃) -69.86(s, 3F), -65.44(t, J ═ 8.8Hz, 1F). ESI-MS M/z calculated 358.1053, Experimental 359.1(M +1)⁺(ii) a Retention time: 2.08min (LC method I).

And 5: 2-tert-butylsulfanyl-6-fluoro-pyridine

2-methylpropane-2-thiol (9.0400g, 11.3mL, 100.24mmol) was added to a suspension of sodium hydride (4.8g, 120mmol, 60% in oil, washed with 20mL of anhydrous ether) in anhydrous tetrahydrofuran (200mL) at 0 deg.C the gray suspension was stirred at room temperature for 30min, followed by the addition of 2, 6-difluoropyridine (10mL, 110.3 mmol). The mixture was stirred at room temperature overnight, then the mixture was cooled with an ice-water bath and then quenched with water the resulting mixture was diluted with ethyl acetate (60mL), washed with water (20mL), brine (20mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-tert-butylsulfanyl-6-fluoro-pyridine as a pale yellow oil (22g, 96% yield, 81% purity) which was used directly in the next step.¹H NMR(300 MHz，CDCl₃)1.55(s, 9H), 6.64(ddd, J ═ 8.1, 2.9, 0.5Hz, 1H), 7.12(dd, J ═ 7.6, 2.2, 0.5Hz, 1H), 7.57(q, J ═ 8.0Hz, 1H), ESI-MS M/z calculated 185.0674, experimental value 186.1 (M +1) ⁺(ii) a Retention time: 2.21min (LC method I).

Step 6: 6-fluoropyridine-2-thiol

To a solution of 2-tert-butylsulfanyl-6-fluoro-pyridine (22g, 81% purity, 96.188 mmol) in 150mL of dichloromethane at room temperature (about 20 deg.C) was added dropwise 100mL (100mmol) of 1M boron tribromideSolution in dichloromethane. The reaction mixture was stirred at room temperature for 2.5 h. Boron tribromide (50.00 mL, 1M in dichloromethane, 50mmol) was additionally added. After 10min, the reaction was diluted with 100mL dichloromethane, washed with water (2 × 100mL), shaken vigorously until two clear phases were obtained, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give crude 6-fluoropyridine-2-thiol as a yellow oil (28g, 100% yield, 45% purity).¹H NMR(300MHz，CDCl₃)6.65(dd，J＝8.1，2.5Hz，1H)，7.07(dd， J＝7.6，2.2Hz，1H)，7.60(q，J＝7.9Hz，1H).¹⁹F NMR(282MHz，CDCl₃)-66.78(s， 1F).

And 7: 2-fluoro-6- [ (6-fluoro-2-pyridyl) disulfanyl ] pyridine

To a solution of 6-fluoropyridine-2-thiol (28g, 45% purity, 97.557mmol) in diethyl ether (160mL) was slowly added bromine (17.063g, 5.5mL, 106.77mmol) at room temperature until it was still orange. The addition was stopped and the reaction mixture was diluted with ethyl acetate (100mL), washed with a 1: 1 mixture of saturated sodium bicarbonate and 10% sodium thiosulfate solution, brine, and concentrated under reduced pressure the residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate/heptane (0% -20%) to give 2-fluoro-6- [ (6-fluoro-2-pyridinyl) disulfanyl as a brown solid ]Pyridine (10.5g, 84%).¹H NMR(300MHz，CDCl₃)6.75(dd， J＝8.0，2.6Hz，1H)，7.49(dd，J＝7.7，2.1Hz，1H)，7.72(q，J＝7.7Hz，1H)。¹⁹F NMR (282MHz，CDCl₃) -66.37(d, J ═ 6.8Hz, 1F). ESI-MS M/z calculated 255.994, Experimental 257.1(M +1)⁺(ii) a Retention time: 2.12min (LC method I).

And 8: 2-fluoro-N- [ (6-fluoro-2-pyridyl) sulfanyl ] -6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide

To 2-fluoro-6- [ (6-fluoro-2-pyridyl) disulfanyl at 0 ℃]To a solution of pyridine (520mg, 2.0289mmol) in anhydrous acetonitrile (4mL) was added slowly bromine (310.25mg, 0.1000mL, 1.9414 mmol). After stirring at the same temperature for 2min, the red solution was added to 2-fluoro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] at 0 ℃]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (720mg, 2.0095mmol) in dry acetonitrile (4mL) and pyridine (6 mL). The resulting dark mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was coevaporated with toluene and purified by silica gel chromatography using a gradient of 0% to 30% ethyl acetate/heptane to give 2-fluoro-N- [ (6-fluoro-2-pyridinyl) sulfanyl) -6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] amide as a white solid]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (700mg, 72%). ESI-MS M/z calculated 485.0945, Experimental 486.1(M +1) ⁺(ii) a Retention time: 2.36min (LC method I).

And step 9: 2-fluoro-N- [ (6-fluoro-2-pyridyl) sulfinyl ] -6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide

Metachloroperoxybenzoic acid (355mg, 77% purity, 1.58mmol) was added to 2-fluoro-N- [ (6-fluoro-2-pyridyl) sulfanyl at 0 deg.C]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (700mg, 1.4420mmol) in dichloromethane (20mL) and the reaction stirred at the same temperature for 1h the reaction mixture was diluted with dichloromethane (70mL), washed successively with 10% w/v aqueous sodium thiosulfate, 5% w/v aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of 0% to 40% ethyl acetate in heptane, to give racemic 2-fluoro-N- [ (6-fluoro-2-pyridinyl) sulfinyl group as a white solid]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (700mg, 97%). ESI-MS M/z calculated 501.0894, Experimental 502.1(M +1)⁺(ii) a Retention time: 2.25min (LC method I).

Step 10: 4- (3-azidopropyl) -2, 2-dimethyl-pyrrolidine (hydrochloride)

Hydrochloric acid (2mL, 4M in 1, 4-dioxane, 8.0mmol) was added to a solution of 4- (3-azidopropyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.2g, 4.2496mmol) in dichloromethane (10mL) cooled with an ice-water bath. The mixture was concentrated under reduced pressure. The residue was co-evaporated twice with toluene (40mL) to give crude 4- (3-azidopropyl) -2, 2-dimethyl-pyrrolidine (hydrochloride) (930mg, 100%) as a pale yellow oil.¹H NMR(300MHz，CDCl₃)1.29(s, 3H), 1.38-1.54 (M, 8H), 1.99(dd, J ═ 12.7, 7.7Hz, 1H), 2.31-2.42(M, 1H), 2.76-2.89(M, 1H), 3.32-3.36(M, 3H), 9.00(br.s., 1H), 9.11(br.s., 1H), ESI-MS M/z calculated 182.1531, experimental 183.2(M +1)⁺(ii) a Retention time: 0.94min (LC method I).

Step 11: 2- [4- (3-azidopropyl) -2, 2-dimethyl-pyrrolidin-1-yl ] -N- [ (6-fluoro-2-pyridyl) sulfinyl ] -6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide

Sodium hydride (193mg, 60% w/w dispersion in mineral oil, 2.6mmol) was added to a solution of 4- (3-azidopropyl) -2, 2-dimethyl-pyrrolidine (hydrochloride) (528mg, 2.4mmol) in anhydrous N, N-dimethylformamide (10mL) cooled with an ice-water bath the mixture was stirred for 5min and 2-fluoro-N- [ (6-fluoro-2-pyridinyl) sulfinyl group was added ]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (930mg, 1.85 mmol.) the mixture was stirred at room temperature for 30min and thenThe mixture was then placed in an oil bath (50 ℃ C.) and stirred for 4 hours. Thereafter, the mixture was allowed to cool and stand overnight. The mixture was diluted with ethyl acetate (100 mL). The resulting mixture was washed with water (3 × 30mL), brine (30mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure the residue was purified by silica gel chromatography using a gradient of 0% to 70% ethyl acetate/heptane to obtain 2- [4- (3-azidopropyl) -2, 2-dimethyl-pyrrolidin-1-yl as a white solid]-N- [ (6-fluoro-2-pyridinyl) sulfinyl]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (600mg, 49%). ESI-MS M/z calculated 663.2363, Experimental 664.3(M +1)⁺(ii) a Retention time: 2.61min (LC method I).

Step 12: 2- [4- (3-azidopropyl) -2, 2-dimethyl-pyrrolidin-1-yl ] -N- [ (6-fluoro-2-pyridyl) sulfoxy (sulfonimidyl) ] -6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide

Ammonia (10mL, 0.5M solution in 1, 4-dioxane, 5mmol) was added to a solution of 2- [4- (3-azidopropyl) -2, 2-dimethyl-pyrrolidin-1-yl ] -N- [ (6-fluoro-2-pyridyl) sulfinyl ] -6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide (580mg, 0.87 mmol) in anhydrous acetonitrile (5mL) at 0 ℃ N-chlorobutyldiimide (140mg, 1.05 mmol) was added all at once (the mixture turned orange) and the reaction was stirred at 0 ℃ for 1h N-chlorobutyldiimide (100mg, 0.75mmol) was added additionally, and the reaction was stirred at the same temperature for 30 min. The reaction was then quenched with 10% w/v aqueous sodium thiosulfate and extracted with ethyl acetate (50 mL). The organic layer was washed with brine (20mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure the residue was purified by silica gel chromatography, eluting with a gradient of 0% to 55% ethyl acetate/heptane, to give 2- [4- (3-azidopropyl) -2, 2-dimethyl-pyrrolidin-1-yl ] -N- [ (6-fluoro-2-pyridyl) sulfoximidoyl ] -6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide as a yellow gummy solid (400mg, 67%).

Step 13: 2- [4- (3-aminopropyl) -2, 2-dimethyl-pyrrolidin-1-yl ] -N- [ (6-fluoro-2-pyridyl) sulfoxy yl ] -6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide

At room temperature under 1atm H₂Under the balloon, 2- [4- (3-azidopropyl) -2, 2-dimethyl-pyrrolidin-1-yl]-N- [ (6-fluoro-2-pyridyl) sulfoxy acyl]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]A mixture of pyridine-3-carboxamide (360mg, 0.5304mmol), ammonia in methanol (7N, 1mL) and methanol (10mL) containing 10% palladium on carbon (moist, Degussa, 200mg, 0.094mmol) was hydrogenated for 3h. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give crude 2- [4- (3-aminopropyl) -2, 2-dimethyl-pyrrolidin-1-yl as a yellow solid]-N- [ (6-fluoro-2-pyridyl) sulfoxy acyl]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (380 mg, 81% yield, 74% purity). the crude product was used in the next step without purification ESI-MS calcd for M/z 652.2567, experimental 653.3(M +1)⁺(ii) a Retention time: 1.70min (LC method I).

Step 14: 2-imino-12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaene-2, 4-dione (diastereomer pair 1) (Compound 262) and 2-imino-12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaene-2, 4-dione (diastereomer pair 2) (Compound 263)

2- [4- (3-aminopropyl) -2, 2-dimethyl-pyrrolidin-1-yl in a sealed tube at 100 ℃]-N- [ (6-fluoro-2-pyridyl) sulfoxy acyl]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]A mixture of pyridine-3-carboxamide (380mg, 0.5822mmol), triethylamine (239.58mg, 0.33mL, 2.3676mmol) and anhydrous dimethylsulfoxide (25mL) was stirred for 4 h. The mixture was cooled to room temperature, then diluted with water (100mL), and extracted with ethyl acetate (3 × 40 mL.) the combined organic layers were washed with water (2 × 30mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0% to 60% ethyl acetate/heptane to obtain 2-imino-12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] propyl as a white solid as the first diastereomer pair of the enantiomer to be eluted ]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaene-2, 4-dione (diastereomer pair 1) (compound 262) (88.76 mg, 23% yield),¹H NMR(300MHz，CDCl₃)ppm 0.72-0.80(m，2H)，0.96-1.05(m， 2H)，1.13-1.23(m，1H)，1.29-1.44(m，1H)，1.59(s，3H)，1.67-1.71(m，1H)，1.75(s， 3H)，1.82-1.94(m，2H)，2.00-2.31(m，4H)，3.09-3.34(m，2H)，3.60(t，J＝11.0Hz，1H)， 3.75-3.94(m，1H)，4.39(t，J＝7.0Hz，2H)，4.70-4.80(m，1H)，5.86(d，J＝2.6Hz，1H)， 6.47(d，J＝8.5Hz，1H)，6.97(d，J＝8.5Hz，1H)，7.02(br.s.，2H)，7.30(d，J＝7.0Hz， 1H)，7.47(dd，J＝8.2，7.3Hz，1H)，8.17(d，J＝8.2Hz，1H)，8.24(d，J＝2.6Hz，1H)。¹⁹F NMR(282MHz，CDCl₃) ppm-70.0(br.s., 3F). ESI-MS M/z calculated 632.2505, Experimental 633.3(M +1)⁺(ii) a Retention time: 3.98min (LC method H) and 2-imino-12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid as the second diastereomer of the enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaene-2, 4-dione (diastereomer pair 2) (compound 263) (97.02mg, 25% yield).¹H NMR(300MHz，CDCl₃)0.70-0.78(m， 2H)，0.97-1.05(m，2H)，1.34-1.46(m，2H)，1.58-1.63(m，7H)，1.64-1.74(m，2H)，1.82(dd，J＝11.3，5.4Hz，1H)，2.08-2.12(m，3H)，2.96-3.11(m，2H)，3.29-3.42(m， 1H)，4.16-4.25(m，1H)，4.32-4.41(m，3H)，5.09(br.s.，2H)，5.84(d，J＝2.6Hz，1H)， 6.53(d，J＝8.5Hz，1H)，6.96(d，J＝8.2Hz，1H)，7.35(d，J＝7.0Hz，1H)，7.53(dd，J＝8.5， 7.3Hz，1H)，8.07(d，J＝8.2Hz，1H)，8.20(d，J＝2.6Hz，1H).¹⁹F NMR(282MHz， CDCl₃) -70.0(s, 3F). ESI-MS M/z calculated 632.2505, Experimental 633.3(M +1)⁺(ii) a Retention time: 3.77min (LC method H).

Example 88: preparation of (14S) -8- [3- (2- { dispiro [ [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-21-hydroxy-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 264)

Step 1: 4-benzyloxy-2-chloro-6-fluoro-pyridine

To a solution of 2-chloro-6-fluoro-pyridin-4-ol (4.62g, 31.315mmol) in acetonitrile (90mL) was added cesium carbonate (15.3g, 46.959mmol) and benzyl bromide (5.8958g, 4.1mL, 34.472 mmol). The reaction was stirred at room temperature overnight the solution was dissolved in ethyl acetate (350mL) and water (100 mL). The aqueous phase was removed and the organic phase was washed with water (100mL) and brine (75 mL). Through the chromatography on silica gel,the crude product was purified by elution with a gradient of 0% to 10% ethyl acetate/heptane to give 4-benzyloxy-2-chloro-6-fluoro-pyridine as a white solid (7.01g, 94%). ESI-MS M/z calculated 237.0357, experimental 238.1(M +1)⁺(ii) a Retention time: 2.38min (LC method N).

Step 2: 3- [ (4-benzyloxy-6-fluoro-2-pyridyl) sulfanyl ] propionic acid 2-ethylhexyl ester

A solution of 4-benzyloxy-2-chloro-6-fluoro-pyridine (6.77g, 28.486mmol) and diisopropylethylamine (7.4200g, 10mL, 57.411mmol) in toluene (250mL) was degassed by bubbling nitrogen for 5min A solution of tris (dibenzylideneacetone) dipalladium (0) (783mg, 0.8551mmol), Xantphos (990mg, 1.7110mmol) and 2-ethylhexyl 3-sulfanylpropionate (6.5280g, 6.8mL, 29.896mmol) was added and the mixture was heated at 125 deg.C overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 0% to 10% ethyl acetate in heptane to give 3- [ (4-benzyloxy-6-fluoro-2-pyridinyl) sulfanyl as an orange oil ]2-ethylhexyl propionate (12.06g, quantitative yield).¹H NMR(300MHz，CDCl₃) 0.80-0.95(m，6H)，1.19-1.43(m，8H)，1.51-1.63(m，1H)，2.77(t，J＝7.0Hz，2H)，3.37 (t，J＝6.9Hz，2H)，4.02(dd，J＝5.9，1.2Hz，2H)，5.07(s，2H)，6.18(d，J＝1.8Hz，1H)， 6.65(d，J＝1.2Hz，1H)，7.28-7.49(m，5H).¹⁹F NMR(282MHz，CDCl₃) 65.7(s, 1F). ESI-MS M/z calculated 419.193, Experimental 420.2(M +1)⁺(ii) a Retention time: 2.8min (LC method I).

And step 3: 3- [ (4-benzyloxy-6-fluoro-2-pyridinyl) sulfonyl ] propionic acid 2-ethylhexyl ester

To 3- [ (4-benzyloxy-6-fluoro-2-pyridinyl) sulfonyl at 0 deg.C]2-ethylhexyl propionate (12.06g, 28.745mmol) in diTo a solution of methyl chloride (150mL) was slowly added m-chloroperbenzoic acid (12.9g, 57.561 mmol). The mixture was stirred at this temperature overnight. Ethyl acetate (150mL) was added and washed with a saturated solution of sodium bicarbonate (100mL) and 0.5M sodium hydroxide solution (2X 100 mL.) the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3- [ (4-benzyloxy-6-fluoro-2-pyridinyl) sulfonyl as a colorless oil]2-ethylhexyl propionate (12.05g, 93%). ESI-MS M/z calculated 451.1829, Experimental 452.2(M +1)⁺(ii) a Retention time: 2.54min (LC method I).

And 4, step 4: 4-benzyloxy-6-fluoro-pyridine-2-sulfonamide

To 3- [ (4-benzyloxy-6-fluoro-2-pyridyl) sulfonyl group]To a solution of 2-ethylhexyl propionate (10.69g, 23.674 mmol) in dimethyl sulfoxide (60mL) was added 1, 8-diazabicyclo [ 5.4.0% ]Undec-7-ene (7.0700 g, 7mL, 46.441 mmol.) the reaction was stirred at room temperature for 1h, and a solution of hydroxylamine-O-sulfonic acid (13.3g, 117.60mmol) and sodium acetate (7.7g, 93.864mmol) in water (40mL) was added at 10 ℃. The reaction was stirred at room temperature for 1h, diluted with water (300mL) and extracted with ethyl acetate (2X 300 mL). The combined organic layers were washed with brine (300mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was triturated overnight with a mixture of heptane/ethyl acetate 9: 1 (100 mL). The product was isolated by filtration. The product was redissolved in ethyl acetate and filtered through a pad of silica gel, eluted with ethyl acetate (500mL) and concentrated to give 4-benzyloxy-6-fluoro-pyridine-2-sulfonamide (5.56g, 83%).¹H NMR (300MHz, dimethylsulfoxide-d)₆) 5.34(s，2H)，7.15(d，J＝2.1Hz，1H)，7.30-7.54(m，6H)，7.62(s，2H).¹⁹F NMR (282 MHz, dimethyl sulfoxide-d)₆) -66.0(s, 1F). ESI-MS M/z calculated 282.0474, Experimental 283.1 (M +1)⁺(ii) a Retention time: 1.75min (LC method I).

And 5: (4S) -4- [3- [ (4-benzyloxy-6-sulfamoyl-2-pyridyl) amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

A20 mL vial was charged with (4S) -4- (3-aminopropyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (312mg, 1.217mmol), 4-benzyloxy-6-fluoro-pyridine-2-sulfonamide (344mg, 1.219 mmol), anhydrous dimethylsulfoxide (3.5mL), and diisopropylethylamine (0.32mL, 1.837mmol) under nitrogen, the vial was capped and stirred at 85 ℃ for 16h, the mixture was diluted with ethyl acetate (50mL), water (50mL), and 10% citric acid (10mL), the two phases were separated, the organic phase was washed with brine (30mL), dried over sodium sulfate, filtered, and the solvent was evaporated (product was purified by chromatography on silica gel using an ethyl acetate/hexane gradient (0% to 70%, over 30min) to give (4S) -4- [3- [ (4-benzyloxyl) as a white foamy solid 6-sulfamoyl-2-pyridyl) amino ]Propyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (427mg, 68%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)7.47-7.29(M, 5H), 7.07(s, 2H), 6.83(t, J ═ 5.4Hz, 1H), 6.66(d, J ═ 2.0Hz, 1H), 6.15(d, J ═ 1.8Hz, 1H), 5.14(s, 2H), 3.55(q, J ═ 9.5Hz, 1H), 3.25 (wide q, J ═ 6.4Hz, 2H), 2.78(q, J ═ 9.9Hz, 1H), 2.10(br s, 1H), 1.94-1.81(M, 1H), 1.57-1.43 (M, 2H), 1.45-1.29(M, 15H), 1.24(s, 3H), ESI-MS M/z, calculated value 518.2563, experimental value + 1.519 (M + 1H)⁺(ii) a Retention time: 1.92min (LC method B).

Step 6: (4S) -4- [3- [ [ 4-benzyloxy-6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1] hept-7-ylethoxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To 2-chloro-6- [3- (2-dispiro [2.0.2.1]]Hept-7-ylethoxy) pyrazol-1-yl]To a stirred solution of pyridine-3-carboxylic acid (130mg, 0.3613mmol) in anhydrous tetrahydrofuran (2mL) was added carbonyldiimidazole(60mg, 0.3700mmol) and stirring at ambient temperature under nitrogen is continued for 2 h. To the reaction was added (4S) -4- [3- [ (4-benzyloxy-6-sulfamoyl-2-pyridyl) amino group]Propyl radical ]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (160mg, 0.3085mmol) in anhydrous tetrahydrofuran (1mL) followed by addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (200 μ L, 1.337mmol) and the mixture stirred at ambient temperature for 15 h the volatiles were removed under reduced pressure and the residue was diluted with ethyl acetate (20mL) and water (20mL) and the mixture was slowly acidified to about pH 4.0 with 4M aqueous hydrochloric acid (350 μ L, 4M, 1.400 mmol). The layers were separated and the aqueous layer was extracted with ethyl acetate (15mL) the combined organic phases were washed with brine (20mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (gradient of 0% -70% ethyl acetate/hexane over 35min) to give (4S) -4- [3- [ [ 4-benzyloxy-6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1 ]) as a white solid]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (72mg, 27%). ESI-MS calculated M/z 859.34937, Experimental 860.6(M +1)⁺(ii) a Retention time: 2.41min (LC method G).

And 7: n- [ [ 4-benzyloxy-6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] propylamino ] -2-pyridinyl ] sulfonyl ] -2-chloro-6- [3- (2-dispiro [2.0.2.1] hept-7-ylethoxy) pyrazol-1-yl ] pyridine-3-carboxamide (trifluoroacetate)

Reaction under nitrogen at ambient temperature to (4S) -4- [3- [ [ 4-benzyloxy-6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1 ]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]To a stirred solution of tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (70mg, 0.08135mmol) in anhydrous dichloromethane (2mL) was added trifluoroacetic acid (300 μ L, 3.894 mmol.) the orange solution was stirred for 1h, followed by removal of volatiles under reduced pressure. Toluene (20mL) was added to the residue and concentrated to dryness under reduced pressure. Repeat the process againTo remove any residual trifluoroacetic acid and finally vacuum drying for 2h to obtain crude N- [ [ 4-benzyloxy-6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] ester]Propylamino group]-2-pyridyl]Sulfonyl radical]-2-chloro-6- [3- (2-dispiro [2.0.2.1 ]]Hept-7-ylethoxy)]Pyrazol-1-yl]Pyridine-3-carboxamide (trifluoroacetate) (71mg, 100%). ESI-MS M/z calculated 759.29694, Experimental 760.5(M +1)⁺(ii) a Retention time: 2.01min (LC method B).

And 8: (14S) -21- (benzyloxy) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione

A20 mL vial was charged with N- [ [ 4-benzyloxy-6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] in that order]Propylamino group]-2-pyridyl]Sulfonyl radical]-2-chloro-6- [3- (2-dispiro [2.0.2.1 ]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carboxamide (trifluoroacetate) (67mg, 0.07663mmol), potassium carbonate (65mg, 0.4703 mmol), cesium fluoride (24mg, 0.1580mmol) and anhydrous dimethyl sulfoxide (5 mL.) the vial was purged with a stream of nitrogen for 2min, capped and stirred at 160 ℃ for 15 h. The reaction was cooled to ambient temperature and the heterogeneous mixture was diluted with ethyl acetate (30mL) and water (20mL) and acidified with hydrochloric acid (1.0mL, 1.0M, 1.000 mmol.) the layers were separated and the aqueous layer re-extracted with ethyl acetate (20 mL.) the combined organics were washed with brine (20mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by silica gel chromatography (0% -10% methanol/dichloromethane over 30min) to give (14S) -21- (benzyloxy) -8- [3- (2- { dispiro [2.0.2.1 ] as a white solid]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (34mg, 61%). ESI-MS M/z calculated 723.3203, Experimental 724.5(M +1) ⁺(ii) a RetentionTime: 2.22min (LC method G).

And step 9: (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-21-hydroxy-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 264)

To (14S) -21- (benzyloxy) -8- [3- (2- { dispiro [2.0.2.1 ] under nitrogen]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]A stirred solution of tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (25mg, 0.03454mmol) in dry methanol (5mL) was added 10% palladium on carbon (moist, Degussa, 12mg, 0.01128mmol) and the heterogeneous mixture stirred under hydrogen (balloon) at ambient temperature for 3 h. The hydrogen balloon was removed and the flask was purged with nitrogen and the black heterogeneous reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure, and the residue was dissolved in dimethyl sulfoxide (1.5mL) and filtered through Whatman 0.45 μm PTFE syringe filter. Use preparative reverse phase HPLC-MS [ Luna C sold by Phenomenex ₁₈(2) Column (75X 30mm, 5 μm particle size) (pn: 00C-4252-U0-AX), (15 min, double gradient run with 30% -99% acetonitrile/water (no modifier)]Purifying the sample to obtain (14S) -8- [3- (2- { dispiro [2.0.2.1 ] as an off-white solid]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-21-hydroxy-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 264) (8 mg, 36%).¹H NMR (400MHz, methanol-d)₄)8.24(d，J＝2.8Hz，1H)，7.85(d，J＝8.2 Hz，1H)，6.97(d，J＝8.2Hz，1H)，6.75(d，J＝1.9Hz，1H)，6.00(d，J＝1.9Hz，1H)， 5.94(d，J＝2.7Hz，1H)，4.24(t，J＝6.6Hz，2H)，4.02(t，J＝13.1Hz，1H)，3.38-3.32 (m，2H)，3.08-2.97(M, 1H), 2.92(t, J ═ 10.5Hz, 1H), 2.24-2.09(M, 1H), 1.88(q, J ═ 6.6Hz, 3H), 1.85-1.76(M, 1H), 1.66(s, 3H), 1.63(d, J ═ 5.7Hz, 2H), 1.60(s, 3H), 1.49(d, J ═ 6.5Hz, 1H), 1.47-1.39(M, 1H), 0.91-0.79(M, 4H), 0.66(ddd, J ═ 8.8, 4.7, 3.4Hz, 2H), 0.58-0.48(M, 2H), ESI-MS M/z calculated value 633.2733, experimental value 634.5 (M +1)⁺(ii) a Retention time: 2.27min (LC method B).

Example 89: preparation of (14S) -21-hydroxy-12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 265)

Step 1: (4S) tert-butyl 4- [3- [ [ 4-benzyloxy-6- [ [ 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylate

To 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]A stirred solution of pyridine-3-carboxylic acid (130mg, 0.3335mmol) in anhydrous tetrahydrofuran (2mL) was added carbonyldiimidazole (55mg, 0.3392mmol) and stirring was continued at ambient temperature under nitrogen for 2 h. To the reaction was added (4S) -4- [3- [ (4-benzyloxy-6-sulfamoyl-2-pyridyl) amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (150mg, 0.2892mmol) in anhydrous tetrahydrofuran (1mL) followed by addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (200 μ L, 1.337mmol) and the mixture was stirred at ambient temperature for 15 h the volatiles were removed under reduced pressure and the residue was diluted with ethyl acetate (20mL) and water (20mL) and washed with 4M aqueous hydrochloric acid (350 μ L, 4M, 1.400mmol)The mixture was slowly acidified to about pH 4.0. The layers were separated and the aqueous layer was extracted with ethyl acetate (15 mL). The combined organic phases were washed with brine (20mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (gradient of 0% to 70% ethyl acetate/hexane over 35min) to give (4S) -4- [3- [ [ 4-benzyloxy-6- [ [ 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] methyl ] phenyl ] ethyl acetate as a white solid ]Propoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (128mg, 50%). ESI-MS calculated M/z 889.3211, Experimental 890.6(M +1)⁺(ii) a Retention time: 2.25min (LC method G).

Step 2: n- [ [ 4-benzyloxy-6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] propylamino ] -2-pyridinyl ] sulfonyl ] -2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carboxamide (trifluoroacetate)

To 4- [3- [ [ 4-benzyloxy-6- [ [ 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] at ambient temperature under nitrogen]Propoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (121mg, 0.1359mmol) to a stirred solution in anhydrous dichloromethane (3mL) trifluoroacetic acid (500 μ L, 6.490mmol) was added, the orange solution was stirred for 1h and then the volatiles were removed under reduced pressure, toluene (20mL) was added to the residue and concentrated to dryness under reduced pressure. The process was repeated again to remove any residual trifluoroacetic acid and finally dried in vacuo for 2h to obtain crude N- [ [ 4-benzyloxy-6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] amine ]Propylamino group]-2-pyridyl]Sulfonyl radical]-2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxamide (trifluoroacetate) (122mg, 99%) this material was used directly in the next step without any purification ESI-MS calcd for M/z 789.2687, experimental 790.5(M +1)⁺(ii) a Retention time: 1.9min (LC method B).

And step 3: (14S) -21- (benzyloxy group) -12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione

A20 mL vial was charged with N- [ [ 4-benzyloxy-6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] in that order]Propylamino group]-2-pyridyl]Sulfonyl radical]-2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxamide (trifluoroacetate salt) (115mg, 0.1272mmol), potassium carbonate (110mg, 0.7959 mmol), cesium fluoride (39mg, 0.2567mmol) and anhydrous dimethyl sulfoxide (9 mL.) the vial was purged with a stream of nitrogen for 2min, capped and stirred at 160 ℃ for 15h. The crude material was purified by silica gel chromatography (gradient of 0% to 10% methanol in dichloromethane over 30min) to give (14S) -21- (benzyloxy) -12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl) as a white solid ]Propoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (54mg, 56%). ESI-MS M/z calculated 753.29205, Experimental 754.5(M +1)⁺(ii) a Retention time: 1.51min (LC method J).

And 4, step 4: (14S) -21-hydroxy-12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Propoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 265)

To (14S) -21- (benzyloxy) -12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl ] under nitrogen]Propoxy } -1H-pyrazol-1-yl]-2λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]To a stirred solution of tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (40mg, 0.05306mmol) in dry methanol (5 mL) was added 10% palladium on carbon (moist, Degussa, 19mg, 0.01785 mmol). The heterogeneous mixture was stirred at ambient temperature under hydrogen (balloon) for 2.5h the hydrogen balloon was removed and the flask was purged with nitrogen and the black heterogeneous reaction mixture was filtered through a pad of celite the filtrate was concentrated under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.5mL) and filtered through a Whatman 0.45 μm PTFE syringe filter. Use preparative reverse phase HPLC-MS [ Luna C sold by Phenomenex ₁₈(2) Column (75X 30mm, 5 μm particle size) (pn: 00C-4252-U0-AX), (15 min, double gradient run with 30% -99% acetonitrile/water (no modifier)]Purifying the sample to obtain (14S) -21-hydroxy-12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl ] as a light blue-green solid]Propoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 265) (16mg, 45%).¹H NMR (400MHz, methanol-d)₄)8.25(d，J＝2.8Hz，1H)，7.85 (d，J＝8.2Hz，1H)，6.97(d，J＝8.2Hz，1H)，6.76(d，J＝1.9Hz，1H)，6.00(d，J＝1.9 Hz，1H)，5.97(d，J＝2.8Hz，1H)，4.24(t，J＝6.1Hz，2H)，4.01(t，J＝12.8Hz，1H)， 3.36-3.32(m，1H)，3.02(d，J＝13.6Hz，1H)，2.94(t，J＝10.5Hz，1H)，2.24-2.08 (m，1H)，1.94(dq，J＝11.0，6.3Hz，2H)，1.90-1.79(m，2H)，1.78(d，J＝4.6Hz，1H)， 1.77-1.74(m，1H)，1.66(s，3H)，1.63(d，J＝7.0Hz，2H)，1.60(s，3H)，1.58(d，J＝ 7.9Hz，1H)，1.51-1.36(m，1H)，0.98-0.92(m，2H)，0.73-0.65(m，2H).¹⁹F NMR (376MHz, methanol-d)₆) Calculated ESI-MS m/z 663.24506, Exp 665.5(M+1)⁺(ii) a Retention time: 2.13min (LC method B).

Example 90: preparation of 2-imino-12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaene-2, 4-dione (diastereomer pair 1, enantiomer 1) (Compound 266), 2-imino-12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaene-2, 4-dione (diastereomer pair 1, enantiomer 2) (Compound 267), 2-imino-12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaene-2, 4-dione (diastereomer pair 2, enantiomer 1) (compound 271) and 2-imino-12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaene-2, 4-dione (diastereomer pair 2, enantiomer 2) (Compound 272)

Step 1: 2-imino-12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaene-2, 4-dione (diastereomer pair 1, enantiomer 1) (compound 266) and 2-imino-12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7,9, 19, 21-Hexaene-2, 4-dione (diastereomer pair 1, enantiomer 2) (Compound 267)

To racemic 2-imino-12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaene-2, 4-dione (81mg, 0.1248mmol) (diastereomer pair 1) (81mg) was subjected to chiral SFC (ChiralPak AD-H (250X 10mM), 5. mu.M column; mobile phase: 34% acetonitrile/methanol (50: 50, 20mM NH)₃) 66% carbon dioxide, 10 mL/min; concentration 12mg/mL in acetonitrile/methanol (50: 5020 mM NH)₃) (ii) a Injection volume 70 μ L, 100 bar) to give 2-imino-12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl) as the first enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaene-2, 4-dione (diastereomer pair 1, enantiomer 1) (compound 266) (15.2mg, 38%), ¹H NMR (400MHz, dimethylsulfoxide-d)₆)8.14(d, J ═ 2.7Hz, 1H), 7.75 (d, J ═ 8.1Hz, 1H), 7.54-7.43(m, 1H), 7.03(t, J ═ 6.8Hz, 2H), 6.77(d, J ═ 8.1Hz, 1H), 6.54(d, J ═ 8.4Hz, 1H), 6.00(d, J ═ 2.6Hz, 1H), 4.24(t, J ═ 7.0Hz, 2H), 3.17 (dd, J ═ 10.8, 7.3Hz, 1H), 2.12(s, 1H), 2.05-1.99(m, 2H), 1.82(s, 2H), 1.53(d, J ═ 26.0, 9H), 1.23(d, J ═ 4.51H), 4.85 (d, J ═ 26.0, 9H); ESI-MS M/z calculated 632.2505, Experimental 633.0(M +1)⁺(ii) a Retention time: 3.16min (LC method D); and 2-imino-12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as the second enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaene-2, 4-dione (non-tetracosane)Enantiomer pair 1, enantiomer 2) (compound 267) (15mg, 38%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)8.21(s, 1H), 7.82(d, J ═ 8.1Hz, 1H), 7.53(s, 1H), 7.09(s, 2H), 6.83(d, J ═ 8.1Hz, 1H), 6.60(d, J ═ 8.3 Hz, 1H), 6.07(s, 1H), 4.30(s, 2H), 3.48(s, 1H), 3.24(s, 1H), 2.20(s, 1H), 2.07(d, J ═ 14.1Hz, 2H), 1.87(s, 2H), 1.59(d, J ═ 25.3Hz, 8H), 1.35(s, 1H), 1.23(s, 2H), 0.92(d, J ═ 27.7Hz, 4H), ESI-MS/z, ESI-M/z, experimental calculated value (84 + 85m) ⁺(ii) a Retention time: 3.18min (LC method D).

Step 2: 2-imino-12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaene-2, 4-dione (diastereomer pair 2, enantiomer 1) (compound 271) and 2-imino-12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaene-2, 4-dione (diastereomer pair 2, enantiomer 2) (Compound 272)

To racemic 2-imino-12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaene-2, 4-dione (diastereomer pair 2) (91mg) was subjected to chiral SFC (Phenomenex LUX-4 (250X 21.2mM), 5. mu.M column; mobile phase: 40% acetonitrile/methanol (90: 10, 20mM NH)₃) 60% carbon dioxide, 70 mL/min; concentration 15mg/mL in acetonitrile/methanol (90: 10; 20mM NH) ₃) (ii) a Injection volume 700 μ L, 100 bar.) the first enantiomer to be eluted was further chromatographed by reverse phase preparative using C₁₈Column and a 15min gradient of 50% to 99% acetonitrile in water containing 10mM ammonium formate to give 2-imino-12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl-2-)]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaene-2, 4-dione (diastereomer pair 2, enantiomer 1) (compound 271) (22.4mg, 50%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)8.19(d, J ═ 2.7Hz, 1H), 7.93(d, J ═ 8.1Hz, 1H), 7.59 to 7.53(m, 1H), 7.41(s, 2H), 7.05(d, J ═ 7.2Hz, 1H), 6.86(t, J ═ 9.5Hz, 2H), 6.65(d, J ═ 8.4Hz, 1H), 4.31(t, J ═ 7.0Hz, 2H), 4.08 to 3.92(m, 1H), 3.20(s, 1H), 2.89(t, J ═ 10.8Hz, 2H), 2.08(q, J ═ 7.0, 6.0Hz, 3H), 1.86 to 1.72(m, 2H), 1.55(d, J ═ 27.92, 1.11H, 1H), 1.11.5 (d, 11.5H), 1.11H, 11H, and d (d, 1H). ESI-MS M/z calculated 632.2505, Experimental 633.0(M +1)⁺(ii) a Retention time: 3.02min (LC method D). the second enantiomer to be eluted, which resulted from the separation in SFC, was 2-imino-12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl-) ]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaene-2, 4-dione (diastereomer pair 2, enantiomer 2) (compound 272) (29.8mg, 67%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)8.19(d, J ═ 2.6Hz, 1H), 7.93(d, J ═ 8.1Hz, 1H), 7.60-7.52 (m, 1H), 7.41(s, 2H), 7.05(d, J ═ 7.2Hz, 1H), 6.85(dd, J ═ 12.7, 8.7Hz, 2H), 6.64(d, J ═ 8.4Hz, 1H), 6.06(d, J ═ 2.6Hz, 1H), 4.31(s, 2H), 3.99(d, J ═ 11.5Hz, 1H), 3.20(s, 1H), 2.91(d, J ═ 10.9Hz, 2H), 2.08(t, J ═ 7.0Hz, 3H), 1.88-1.71(m, 2H), 2.91(d, J ═ 10.9Hz, 2H), 2.08(t, J ═ 7.0Hz, 3H, 1H), 1.88-1.92 (m, 2H), 1.55(d, 1H), 1H, 1, d, 1H. ESI-MS M/z calculated 632.2505, Experimental 633.0(M +1)⁺(ii) a Retention time: 3.07min (LC method D).

Example 91: preparation of (14S) -12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl]-3, 3-dideuterio-propoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5(10), 6, 8, 19(23), 20-hexaen-2, 2, 4-trione (compound 269)

Step 1: dideutero- [1- (trifluoromethyl) cyclopropyl ] methanol

To a suspension of lithium aluminum deuteride (2.86g, 71.563mmol) in anhydrous tetrahydrofuran (100mL) was added dropwise a solution of 1- (trifluoromethyl) cyclopropanecarboxylic acid (10g, 64.898mmol) in anhydrous tetrahydrofuran (50mL) at 0 ℃ the reaction mixture was stirred at room temperature for 16h. The reaction was diluted with diethyl ether (100mL) and quenched at 0 ℃ with water (2.9mL), 15% sodium hydroxide (2.9mL), and water (8.7mL) in that order. The reaction mixture was stirred at room temperature for 30min, the white solid was filtered off through a pad of celite and the filtrate was concentrated in vacuo to give dideutero- [1- (trifluoromethyl) cyclopropyl ] as a clear liquid]Methanol (10.855g, 86%).¹H NMR(250MHz，CDCl₃) 1.72(s，1H)，1.03(m，2H)，0.79(m，2H)。

Step 2: [ Dideuterium- [1- (trifluoromethyl) cyclopropyl ] methyl ] methanesulfonate

To dideutero- [1- (trifluoromethyl) cyclopropyl at 0 DEG C]To a solution of methanol (8.537g, 54.064mmol) and triethylamine (10.942g, 15.072mL, 108.13mmol) in dichloromethane (100mL) was added methanesulfonyl chloride (7.4318g, 5.0215mL, 64.877mmol) dropwise. The reaction mixture was stirred at room temperature for 16h, the reaction mixture was washed with 10% citric acid (50mL), saturated sodium bicarbonate (50mL), and brine (50 mL). The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. By silica gel Chromatography, purification of the residue using a gradient of 0% to 70% diethyl ether/hexane, to give [ dideuterio- [1- (trifluoromethyl) cyclopropyl ] as a clear liquid]Methyl radical]Methane sulfonate (11.203g, 88%).¹H NMR(250MHz，CDCl₃)3.06(s，3H)，1.21 (m，2H)，1.02-0.81(m，2H)。

And step 3: 2, 2-dideuterio-2- [1- (trifluoromethyl) cyclopropyl ] acetonitrile

To [ dideutero- [1- (trifluoromethyl) cyclopropyl group]Methyl radical]To a solution of methanesulfonate (11.203g, 47.823mmol) in dimethyl sulfoxide (55mL) was added sodium cyanide (2.9296g, 59.779mmol). The reaction mixture was stirred at 70 ℃ for 24h. After cooling to room temperature, water (50mL) and diethyl ether (50mL) were added to the reaction mixture. The two layers were separated. The aqueous layer was extracted with diethyl ether (2X 70 mL). The combined organic layers were washed with water (2X 50mL) and brine (50mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 2, 2-dideuterio-2- [1- (trifluoromethyl) cyclopropyl ] as a yellow liquid]Acetonitrile (6.828g, 84%).¹H NMR(250MHz，CDCl₃)1.18(m，2H)，0.93(s，2H).

And 4, step 4: 2, 2-dideuterio-2- [1- (trifluoromethyl) cyclopropyl ] acetic acid

To 2, 2-dideuterio-2- [1- (trifluoromethyl) cyclopropyl]Acetonitrile (6.828g, 40.211mmol) in CH₃Cwater D (70mL) was added a solution of sodium deuteroxide (16.487g, 40% w/w, 160.84 mmol) in deuterium oxide (16mL), the reaction mixture was stirred at 70 ℃ for 24h, cooled to room temperature, and CH was removed under reduced pressure ₃The solvent was diluted with water (70mL) and washed with diethyl ether (2 × 50 mL.) the aqueous layer was acidified to pH 1 with 6N hydrochloric acid and then extracted with diethyl ether (3 × 70 mL). The combined organic layers were washed with brine (50mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressureTo obtain 2, 2-dideuterio-2- [1- (trifluoromethyl) cyclopropyl ] as a yellow liquid]Acetic acid (6.387g, 83%).¹H NMR(250 MHz，CDCl₃)1.18-1.05(m，2H)，0.93-0.79(m，2H)。

And 5: 2, 2-dideuterio-2- [1- (trifluoromethyl) cyclopropyl ] ethanol

To a suspension of lithium aluminum hydride (952.12mg, 1.0383mL, 25.086mmol) in anhydrous tetrahydrofuran (50mL) at 0 deg.C was added 2, 2-dideuterio-2- [1- (trifluoromethyl) cyclopropyl dropwise]A solution of acetic acid (3.35g, 19.297 mmol) in dry tetrahydrofuran (50mL) the reaction mixture was stirred at room temperature for 16 h. The reaction was diluted with diethyl ether (50mL) and cooled to 0 ℃. Water (1mL), 15% aqueous sodium hydroxide solution (1mL), and water (3mL) were added in this order, and the resulting mixture was stirred at room temperature for 15 min. Anhydrous magnesium sulfate was added and the reaction mixture was stirred at room temperature for another 15 min. The solid was filtered off and the filtrate was concentrated in vacuo to give 2, 2-dideuterio-2- [1- (trifluoromethyl) cyclopropyl as a clear liquid]Ethanol (3.154g, 84%). ¹H NMR(250MHz，CDCl₃)3.79(s，2H)，1.05-0.78(m，2H)，0.78-0.41(m，2H)。

Step 6: [2, 2-dideuterio-2- [1- (trifluoromethyl) cyclopropyl ] ethyl ] methanesulfonate

To 2, 2-dideuterio-2- [1- (trifluoromethyl) cyclopropyl]Ethanol (3.154g, 16.160mmol) in dichloromethane (32mL) triethylamine (4.9057g, 6.7572mL, 48.480mmol) was added, the reaction mixture was cooled to 0 ℃ and methanesulfonyl chloride (2.2214g, 1.5009mL, 19.392mmol) was added dropwise, the reaction mixture was stirred at room temperature for 2 days, the reaction was diluted with dichloromethane (50mL) and washed with 10% aqueous citric acid (50mL), saturated sodium bicarbonate (50mL) and brine (50mL), the solution was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuoChromatography, purification of the residue using a gradient of 0% to 50% diethyl ether/hexane, afforded [2, 2-dideuterio-2- [1- (trifluoromethyl) cyclopropyl ] as a clear liquid]Ethyl radical]Methane sulfonate (3.28g, 82%).¹H NMR(250MHz，CDCl₃)4.36(s，2H)，3.20-2.87(s，3H)，1.15- 0.94(m，2H)，0.79-0.59(m，2H).

And 7: 3, 3-dideuterio-3- [1- (trifluoromethyl) cyclopropyl ] propionitrile

To [2, 2-dideuterio-2- [1- (trifluoromethyl) cyclopropyl group]Ethyl radical]To a solution of methanesulfonate (3.28g, 13.303mmol) in dimethyl sulfoxide (17mL) was added sodium cyanide (858mg, 16.6 mmol). The reaction mixture was stirred at 70 ℃ for 16h after cooling to room temperature, the reaction mixture was poured into water (30 mL). The mixture was extracted with diethyl ether (3X 50mL) the combined organic layers were washed with water (2X 30mL) and brine (50mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 3, 3-didedeuterium-3- [1- (trifluoromethyl) cyclopropyl ] as a clear liquid ]Propionitrile (2.267g, 99%).¹H NMR(250MHz，CDCl₃)2.54(s，2H)，1.14-1.00(m， 2H)，0.80-0.66(m，2H)。

And 8: 3, 3-dideuterio-3- [1- (trifluoromethyl) cyclopropyl ] propanoic acid

To 3, 3-dideuterio-3- [1- (trifluoromethyl) cyclopropyl]To a solution of propionitrile (2.267g, 13.178mmol) in ethanol (34mL) was added a solution of sodium hydroxide (2.1083g, 52.712mmol) in water (9mL) and the reaction mixture was stirred at 70 ℃ for 20 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo, then diluted with water (30mL), the aqueous solution was washed with diethyl ether (2 × 30mL), and then acidified to pH 1 with 6N hydrochloric acid (aq). The aqueous solution was extracted with diethyl ether (3X 50mL) the combined organic layers were washed with brine (30mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure,to obtain 3, 3-dideuterio-3- [1- (trifluoromethyl) cyclopropyl group as light yellow liquid]Propionic acid (2.652g, 92%).¹H NMR(250MHz，CDCl₃)2.55(s， 2H)，1.07-0.82(m，2H)，0.61(m，2H).

And step 9: 3, 3-dideuterio-3- [1- (trifluoromethyl) cyclopropyl ] propan-1-ol

To a suspension of lithium aluminum hydride (628mg, 14.940mmol) in anhydrous tetrahydrofuran (20mL) was added 3, 3-dideuterio-3- [1- (trifluoromethyl) cyclopropyl dropwise at 0 deg.C]A solution of propionic acid (2.652g, 12.097mmol) in anhydrous tetrahydrofuran (20mL) the reaction mixture was stirred at room temperature for 16 h. The reaction was diluted with diethyl ether (20mL) and cooled to 0 ℃. To the reaction mixture were added water (0.63mL), 15% aqueous sodium hydroxide (0.63mL), and water (1.9mL) in that order. The reaction mixture was stirred at room temperature for 15min, then magnesium sulfate was added and the reaction was stirred at room temperature for a further 15min, the white precipitate was filtered off, the filtrate was concentrated under reduced pressure to give 3, 3-dideuterio-3- [1- (trifluoromethyl) cyclopropyl as a clear liquid ]Propan-1-ol (1.78g, 82%).¹H NMR (250MHz, dimethylsulfoxide-d)₆)4.45(t，J＝5.1Hz，1H)，3.46-3.36(m，2H)，1.50(t，J＝6.2Hz，2H)， 0.86(m，2H)，0.69(m，2H).

Step 10: 3- [3, 3-Dideuterium-3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazole-1-carboxylic acid tert-butyl ester

To 5-oxo-1H-pyrazole-2-carboxylic acid tert-butyl ester (910mg, 4.940mmol) and 3, 3-didehydro-3- [1- (trifluoromethyl) cyclopropyl]To a solution of propan-1-ol (880mg, 5.171mmol) in tetrahydrofuran (11.25mL) was added triphenylphosphine (1.36g, 5.185 mmol). Diisopropyl azodicarboxylate (1.05g, 5.193mmol) was added slowly dropwise to the mixture over 5 min. The reaction mixture was stirred at room temperature for 30min, the tetrahydrofuran was removed in vacuo, chromatographed on silica gel using 100% hexane toThe crude product was purified by a gentle gradient of 20% ethyl acetate in hexane to provide 3- [3, 3-dideuterio-3- [1- (trifluoromethyl) cyclopropyl ] as a colorless oil]Propoxy group]Pyrazole-1-carboxylic acid tert-butyl ester (1.1g, 66%).¹H NMR (400MHz, chloroform-d) 7.83(d, J ═ 3.0Hz, 1H), 5.85(d, J ═ 3.0Hz, 1H), 4.27(t, J ═ 6.2Hz, 2H), 1.90(t, J ═ 6.4Hz, 2H), 1.61(s, 9H), 1.00-0.91 (M, 2H), 0.64-0.50(M, J ═ 1.6Hz, 2H), ESI-MS M/z calculated value 336.163, experimental value 337.2(M +1)⁺(ii) a Retention time: 2.03min (LC method E).

Step 11: 3- [3, 3-dideuterio-3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] -1H-pyrazole

To a solution containing 3- [3, 3-dideuterio-3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]After dichloromethane (22mL) and trifluoroacetic acid (6.3mL, 81.77mmol) were added to a flask of pyrazole-1-carboxylic acid tert-butyl ester (1.1g, 3.270mmol), 30 min, the mixture was evaporated to dryness and neutralized with a saturated aqueous solution of sodium bicarbonate. The reaction was extracted with ethyl acetate and the organic layer was dried over sodium sulfate, filtered and evaporated to give 3- [3, 3-dideuterio-3- [1- (trifluoromethyl) cyclopropyl ] as a colorless oil]Propoxy group]-1H-pyrazole (762mg, 99%). ESI-MS M/z calculated 236.11055, Experimental 237.2(M +1)⁺(ii) a Retention time: 1.43min (LC method E).

Step 12: 2-chloro-6- [3- [3, 3-dideuterio-3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carboxylic acid tert-butyl ester

2, 6-dichloropyridine-3-carboxylic acid tert-butyl ester (800mg, 3.224mmol), 3- [3, 3-dideutero-3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]-1H-pyrazole (762mg, 3.226mmol) and potassium carbonate (1.1g, 7.959mmol) in dry dimethyl sulfoxide (22.0 mL.) 1, 4-diazabicyclo [2.2.2 ] was added]Octane (72.5mg, 0.6463mmol) and under nitrogenThe mixture was stirred at room temperature under air for 18 h. The reaction mixture was diluted with water (16mL) and stirred for 15min the resulting solid formed was filtered, collected and dried under high vacuum. The remaining filtrate was diluted with ethyl acetate and washed with water (3X 20 mL). The organic layers were combined and washed with brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 100% hexanes to 60% ethyl acetate/hexanes to give a light yellow oil, which was then dried in vacuo to give a light yellow solid. Combining the purified solid with the solid from the initial filtration to obtain 2-chloro-6- [3- [3, 3-dideuterio-3- [1- (trifluoromethyl) cyclopropyl ]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (1.36g, 94%).¹H NMR (400MHz, chloroform-d) 8.35(d, J ═ 2.8Hz, 1H), 8.18(d, J ═ 8.4Hz, 1H), 7.68(d, J ═ 8.4Hz, 1H), 5.95(d, J ═ 2.8Hz, 1H), 4.26(t, J ═ 6.2Hz, 2H), 1.95(t, J ═ 6.2Hz, 2H), 1.62(s, 9H), 1.02-0.94(m, 2H), 0.66-0.55(m, J ═ 1.8Hz, 2H). ESI-MS M/z calculated 447.15054, Experimental 448.2(M +1)⁺(ii) a Retention time: 2.49min (LC method E).

Step 13: 2-chloro-6- [3- [3, 3-dideuterio-3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carboxylic acid

2-chloro-6- [3- [3, 3-dideuterio-3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (1.36g, 3.037mmol) was dissolved in dichloromethane (30 mL). To the mixture was added trifluoroacetic acid (5.0mL, 64.90mmol) slowly and the mixture was kept stirring at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to a solid which was then slurried in diethyl ether and filtered, then the solid was reslurried in diethyl ether and filtered to give a solid which was recrystallized from dichloromethane followed by vacuum drying for 20h to give 2-chloro-6- [3- [3, 3-dideuterio-3- [1- (trifluoromethyl) cyclopropyl ] as a white solid ]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxylic acid (1.055g, 89%).ESI-MS M/z calculated 391.08795, experimental 392.2(M +1)⁺(ii) a Retention time: 1.35min (LC method E).

Step 14: (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [3, 3-didehydro-3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- [3, 3-dideuterio-3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxylic acid (250mg, 0.6381mmol) and freshly recrystallized carbonyldiimidazole (120mg, 0.7401mmol) were combined in tetrahydrofuran (6.0mL) and stirred at room temperature for 2 h. Subsequently, (4S) -2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino group is added]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (303mg, 0.7345mmol) followed by addition of anhydrous 1, 8-diazabicyclo [5.4.0]Undec-7-ene (240 μ L, 1.605mmol) and the reaction stirred at room temperature for 24h. Filtration and evaporation followed by silica gel chromatography using a gradient of 100% hexane to 100% ethyl acetate afforded (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [3, 3-didehydro-3- [1- (trifluoromethyl) cyclopropyl) as a white solid ]Propoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (259mg, 52%). ESI-MS M/z calculated 785.2918, Experimental 786.2(M +1)⁺(ii) a Retention time: 2.06min (LC method E).

Step 15: (14S) -12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl ] methyl ester]-3, 3-dideuterio-propoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5(10), 6, 8, 19(23), 20-hexaen-2, 2, 4-trione (compound 269)

Reacting (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [3, 3-didehydro-3- [1- (trifluoromethyl) cyclopropyl)]Propoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (228mg, 0.2900mmol) was dissolved in dichloromethane (7mL) and trifluoroacetic acid (900 μ L, 11.68mmol) was added to the mixture and stirred at room temperature for 15 min. The mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate, and then a saturated aqueous solution of sodium hydrogencarbonate (10mL) was added. The layers were separated and the aqueous layer was further extracted with ethyl acetate (2 × 10 mL.) the organic layers were combined, washed with brine, then dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure the resulting material, potassium carbonate (205mg, 1.483mmol),

Molecular sieves and dimethylsulfoxide (9.5mL) were combined in a vial, purged with nitrogen, capped, heated to 150 ℃, and stirred for 16h. The residue was purified by silica gel chromatography using a gradient from 100% hexane to 100% ethyl acetate followed by a second silica gel column using a gradient from 100% dichloromethane to 10% methanol/dichloromethane to give (14S) -12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl ] as a white solid]-3, 3-dideuterio-propoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5(10), 6, 8, 19(23), 20-hexaen-2, 2, 4-trione (compound 269) (44.8mg, 24%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.51(s，1H)，8.21(d，J＝2.8Hz，1H)，7.81(d，J＝ 8.3Hz，1H)，7.57(t，J＝7.9Hz，1H)，7.05(d，J＝7.2Hz，1H)，6.98(s，1H)，6.91(d，J ＝8.2Hz，1H)，6.71(d，J＝8.6Hz，1H)，6.12(d，J＝2.8Hz，1H)，4.20(t，J＝6.3Hz， 2H)，3.92(d，J＝12.0Hz, 1H), 3.17(d, J ═ 5.2Hz, 1H), 2.95(d, J ═ 13.3Hz, 1H), 2.69(d, J ═ 15.6Hz, 1H), 2.10(d, J ═ 18.7Hz, 1H), 1.83(t, J ═ 6.2Hz, 3H), 1.79-1.69 (M, 1H), 1.60(s, 4H), 1.57(d, J ═ 12.5Hz, 2H), 1.51(s, 3H), 1.37-1.22(M, 2H), 0.93-0.89(M, 2H), 0.75(t, J ═ 1.6Hz, 2H), calculated value ESI-MS M/z 649.2627, experimental value 650.2(M + 1H) ⁺(ii) a Retention time: 2.27min (LC method E).

Example 92: preparation of (14S) -12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl]-2, 2-dideuterio-propoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 270)

Step 1: 1, 1-dideuterio-2- [1- (trifluoromethyl) cyclopropyl ] ethanol

To a suspension of lithium aluminum deuteride (1.0265g, 25.684mmol) in anhydrous tetrahydrofuran (50mL) at 0 deg.C was added 2- [1- (trifluoromethyl) cyclopropyl ] dropwise]A solution of acetic acid (3.954g, 19.757mmol) in dry tetrahydrofuran (50mL) was stirred at room temperature for an additional 16 h. The reaction mixture was diluted with diethyl ether (50mL) and cooled to 0 ℃. To the reaction mixture was added water (1mL), 15% sodium hydroxide (aq) (1mL), and water (3mL) at 0 ℃. The reaction was stirred at room temperature for 15 min. Anhydrous magnesium sulfate was added to the reaction mixture. The reaction was stirred for a further 15 min. The white precipitate was removed by suction filtration and the solvent was removed under reduced pressure to give 1, 1-dideuterio-2- [1- (trifluoromethyl) cyclopropyl ] as a pale yellow oil]Ethanol (3.629g, 82%). ¹H NMR (250MHz, chloroform-d) 1.83(s, 2H), 1.43(s, 1H), 1.04-0.91(m, 2H), 0.72-0.62 (m, 2H).

Step 2: [1, 1-dideuterio-2- [1- (trifluoromethyl) cyclopropyl ] ethyl ] methanesulfonate

To the 1, 1-dideuterio-2- [1- (trifluoromethyl) cyclopropyl group]Ethanol (3.629g, 16.269mmol) in dichloromethane (36mL) was added triethylamine (4.9388g, 6.8028mL, 48.807mmol), the mixture was cooled to 0 deg.C, methanesulfonyl chloride (2.2364g, 1.5111mL, 19.523mmol) was added dropwise to the reaction mixture, the reaction mixture was stirred at room temperature for 3h, the reaction mixture was diluted with dichloromethane (100mL), and washed with 10% aqueous citric acid (30mL), saturated aqueous sodium bicarbonate (30mL), and brine (30mL), the organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, the crude product was purified by silica gel chromatography using a gradient of 0% to 70% diethyl ether/hexane to give [1, 1-didehydro-2- [1- (trifluoromethyl) cyclopropyl ] in a clear liquid]Ethyl radical]Methane sulfonate (3.413g, 90%).¹H NMR (250MHz, chloroform-d) 3.02(s, 3H), 2.02(s, 2H), 1.14-0.95(m, 2H), 0.81-0.63(m, 2H).

And step 3: 2, 2-dideuterio-3- [1- (trifluoromethyl) cyclopropyl ] propionitrile

To [1, 1-dideuterio-2- [1- (trifluoromethyl) cyclopropyl group ]Ethyl radical]To a solution of the methanesulfonate (3.413g, 14.571mmol) in dimethyl sulfoxide (17mL) was added sodium cyanide (892.62mg, 18.214mmol). The reaction mixture was stirred at 70 ℃ for 16h, cooled to room temperature, and, after cooling, the reaction mixture was diluted with water (30mL) and extracted with diethyl ether (3X 30 mL). The combined organic layers were washed with water (2X 30mL) and brine (30mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo the residue was purified by silica gel chromatography using a gradient of 0% to 50% diethyl ether/pentane to give 2, 2-didedeuterium-3- [1- (trifluoromethyl) cyclopropyl ] amine as a clear liquid]Propionitrile (2.181g, 81%).¹H NMR (250MHz, chloroform-d) 1.92(s, 2H), 1.14-1.01(m, 2H), 0.74 (m)，2H)。

And 4, step 4: 2, 2-dideuterio-3- [1- (trifluoromethyl) cyclopropyl ] propanoic acid

To the 2, 2-dideuterio-3- [1- (trifluoromethyl) cyclopropyl group]Propionitrile (2.181g, 11.753mmol) in CH₃Addition of D to solution in Cwater D (30mL)₂O (4mL) and D containing deuterium sodium oxide₂O (4.8191g, 40% w/w, 47.012 mmol). The reaction mixture was stirred at 70 ℃ for 20 h. Removal of CH under reduced pressure₃Cwaterford. By D₂The resulting solution was diluted with O (20mL) and washed with diethyl ether (2X 20 mL). The aqueous solution was then acidified to pH 1 with 6N hydrochloric acid and then extracted with diethyl ether (3 × 20 mL.) the combined organic layers were washed with brine (20mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 2, 2-dideuterio-3- [1- (trifluoromethyl) cyclopropyl as an amber liquid ]Propionic acid (1.945g, 89%).¹H NMR (250MHz, chloroform-d) 1.89(s, 2H), 1.10-0.88(m, 2H), 0.75-0.52(m, 2H).

And 5: 2, 2-dideuterio-3- [1- (trifluoromethyl) cyclopropyl ] propan-1-ol

To a suspension of lithium aluminum hydride (521.15mg, 0.5683mL, 13.731mmol) in anhydrous tetrahydrofuran (20mL) at 0 deg.C was added 2, 2-dideuterio-3- [1- (trifluoromethyl) cyclopropyl ] dropwise]A solution of propionic acid (1.945g, 10.562 mmol) in tetrahydrofuran (20mL) the reaction mixture was stirred at room temperature for 16 h. The reaction was diluted with diethyl ether (30mL) and quenched at 0 ℃ with water (0.53mL), 15% aqueous sodium hydroxide (0.53mL), and water (1.59 mL). The reaction mixture was stirred at room temperature for 30min, and then anhydrous magnesium sulfate was added and stirred for a further 15min the solids were filtered off and the filtrate was concentrated in vacuo to give 2, 2-didedeuterium-3- [1- (trifluoromethyl) cyclopropyl as a clear liquid]Propan-1-ol (1.423g, 75%).¹H NMR (250MHz, dimethylsulfoxide-d)₆)4.44(t， J＝5.1Hz，1H)，3.38(s，2H)，1.57(s，2H)，0.87(t，J＝5.8Hz，2H)，0.69(s，2H)。

Step 6: 3- [2, 2-Dideuterium-3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazole-1-carboxylic acid tert-butyl ester

To a mixture of tert-butyl 5-oxo-1H-pyrazole-2-carboxylate (775mg, 4.208mmol) and 2, 2-dideuterio-3- [1- (trifluoromethyl) cyclopropyl]To a solution of propan-1-ol (750mg, 4.407mmol) in tetrahydrofuran (10mL) was added triphenylphosphine (1.156g, 4.407 mmol). Diisopropyl azodicarboxylate (870 μ L, 4.419mmol) was added slowly dropwise over 10min to the mixture. The reaction mixture was stirred at room temperature for 30min, followed by stirring at 50 ℃ for 30 min. The tetrahydrofuran was removed and the residue was purified by silica gel chromatography using a gentle gradient of 100% hexane to 20% ethyl acetate/hexane to provide 3- [2, 2-dideutero-3- [1- (trifluoromethyl) cyclopropyl ] as a colorless oil ]Propoxy group]Pyrazole-1-carboxylic acid tert-butyl ester (0.998g, 71%).¹H NMR (400MHz, chloroform-d) 7.83(d, J ═ 2.9Hz, 1H), 5.85(d, J ═ 2.9Hz, 1H), 4.26(s, 2H), 1.70(s, 2H), 1.61(s, 9H), 0.99 to 0.93(m, 2H), 0.62 to 0.56(m, 2H). ESI-MS M/z calculated 336.163, Experimental 337.2(M +1)⁺(ii) a Retention time: 1.96min (LC method B).

And 7: 3- [2, 2-dideuterio-3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] -1H-pyrazole

To a solution containing 3- [2, 2-dideuterio-3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazole-1-carboxylic acid tert-butyl ester (998 mg, 2.967mmol) in a round-bottomed flask was added dichloromethane (20mL) and trifluoroacetic acid (5.7mL, 73.98 mmol). after 5min, the reaction was evaporated to dryness and neutralized with a saturated solution of sodium bicarbonate. The reaction was extracted with ethyl acetate, the organic layer was dried over sodium sulfate, filtered and evaporated to afford a colorless solid3- [2, 2-dideuterio-3- [1- (trifluoromethyl) cyclopropyl ] oil]Propoxy group]-1H-pyrazole (700mg, 100%).¹H NMR (400MHz, chloroform-d) 7.36(d, J ═ 2.6Hz, 1H), 5.73(d, J ═ 2.5Hz, 1H), 4.13(d, J ═ 1.6 Hz, 2H), 1.72(s, 2H), 0.99-0.93(M, 2H), 0.63-0.56(M, 2H), ESI-MS M/z calculated 236.11055, experimental 237.1(M +1) ⁺(ii) a Retention time: 1.41min (LC method B).

And 8: 2-chloro-6- [3- [2, 2-dideuterio-3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carboxylic acid tert-butyl ester

Reacting 3- [2, 2-dideuterio-3- [1- (trifluoromethyl) cyclopropyl at room temperature]Propoxy group]-1H-pyrazole (700mg, 2.963 mmol), tert-butyl 2, 6-dichloropyridine-3-carboxylate (742mg, 2.991mmol), potassium carbonate (501mg, 3.625 mmol) and 1, 4-diazabicyclo [2.2.2 mmol ]]A mixture of octane (71mg, 0.6330mmol) in dimethylsulfoxide (5mL) was stirred for 15h. The combined extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. Purifying the residue by silica gel column chromatography with a gradient of 100% hexane to 20% ethyl acetate/hexane to obtain 2-chloro-6- [3- [2, 2-dideuterio-3- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (472mg, 36%).¹H NMR (400MHz, fluoroform-d) 8.35(d, J ═ 2.8Hz, 1H), 8.18(d, J ═ 8.4Hz, 1H), 7.68(d, J ═ 8.4Hz, 1H), 5.95(d, J ═ 2.8Hz, 1H), 4.25(s, 2H), 1.74(s, 2H), 1.61(s, 9H), 1.02-0.94 (M, 2H), 0.63-0.57(M, 2H), ESI-MS M/z calculated 447.15054, experimental 448.23 (M +1) ⁺(ii) a Retention time: 0.95min (LC method A).

And step 9: (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [2, 2-didehydro-3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- [2, 2-dideuterio-3- [1- (trifluoromethyl) cyclopropyl at room temperature]Propoxy group]Pyrazol-1-yl]A solution of pyridine-3-carboxylic acid tert-butyl ester (250mg, 0.5582mmol) in dichloromethane (1.5mL) and trifluoroacetic acid (500 μ L, 6.490mmol) was stirred for 4h then the solvent was removed and the residue dried in vacuo the resulting residue was dissolved in tetrahydrofuran (2mL) and carbonyldiimidazole (102mg, 0.6291mmol) was added and the mixture was stirred at room temperature for 2 h. Subsequently, (4S) -2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino group is added]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (255mg, 0.6181mmol) was added followed by 1, 8-diazabicyclo [5.4.0]Undec-7-ene (130. mu.L, 0.8693mmol) and the reaction stirred for 16 h. The reaction was diluted with ethyl acetate and diluted with a small amount of 1: 1 saturated aqueous ammonium chloride solution/brine the organics were separated, dried over sodium sulfate, filtered and evaporated the resulting brown residue was purified by silica gel chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate to give (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [2, 2-didehydro-3- [1- (trifluoromethyl) cyclopropyl ] as a white solid ]Propoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (172mg, 39%). ESI-MS M/z calculated 785.2918, Experimental 786.4(M +1)⁺(ii) a Retention time: 0.93min (LC method A).

Step 10: (14S) -12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl ] methyl ester]-2, 2-dideuterio-propoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 270)

(4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [2, 2-didehydro-3- [1- (trifluoromethyl) cyclopropyl ] at room temperature]Propoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridinesBase of]Amino group]Propyl radical]A solution of tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (170mg, 0.2162mmol) in dichloromethane (1.2mL) and trifluoroacetic acid (400. mu.L, 5.227 mmol) was stirred for 4 h. The solvent was then removed and the residue dissolved in ethyl acetate the mixture was washed with 2mL of saturated solution of sodium bicarbonate and the organic layer was collected and the solvent removed in vacuo the resulting residue was dissolved in dimethyl sulfoxide (8mL) and the solvent added

Molecular sieves and stir the reaction mixture for 10 min. Subsequently, cesium fluoride (101mg, 0.6649mmol) and potassium carbonate (96mg, 0.6946mmol) were added and the reaction mixture was heated at 150 ℃ for 16 h. The reaction mixture was filtered through Whatman filter disc (puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS method using a double gradient run of 30% to 99% mobile phase B over 15.0min (mobile phase a ═ water (0.05% hydrochloric acid), mobile phase B ═ acetonitrile) to give (14S) -12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl) as an off-white solid ]-2, 2-dideuterio-propoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 270) (62.4mg, 44%).¹H NMR (400 MHz, chloroform-d) 9.87(s, 1H), 8.19(d, J ═ 2.8Hz, 1H), 8.04(d, J ═ 8.3Hz, 1H), 7.56-7.44 (m, 2H), 7.23(d, J ═ 8.4Hz, 1H), 6.55(dd, J ═ 8.2, 1.0Hz, 1H), 5.91(d, J ═ 2.8Hz, 1H), 4.71(dd, J ═ 8.6, 3.4Hz, 1H), 4.24(s, 2H), 3.89(s, 1 ddh), 3.33 (J ═ 10.1, 7.4Hz, 1H), 3.15(dd, J ═ 14.0, 3.6, 1H), 3.05(t, t ═ 9.05, J ═ 10.1, 7.4Hz, 1H), 3.15(dd, J ═ 14.0, 3.0, 7.06H, 7.5.5.7.7.7.7H), 3.15(dd, 7.7.7.15 (dd, 7.7, 7, 7.7.0, 7, 7.7, 7, experimental value 650.12(M +1)⁺(ii) a Retention time: 1.75min (LC method G).

Example 93: preparation of (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-bis (trideuterio) methyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05，10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 274)

Step 1: 3- [3, 3, 3-Trideuterium-2-nitro-2- (Trideuteromethyl) propyl ] tetrahydropyran-2-one

1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene (7.7mL, 51.3mmol) was added to a mixture of 1, 1, 1, 3, 3, 3-hexadeuterium-2-nitro-propane (CDN Isotips, Quebec, Canada) (23.4g, 246.2mmol) and 3-methylene-tetrahydropyran-2-one (23.0g, 205.2 mmol). The reaction is exothermic: after the initial heat evolution dissipated, the mixture was heated in an oil bath at 80 ℃ for 18h, then cooled to room temperature and diluted with 1M hydrochloric acid (100mL) and dichloromethane (500 mL.) the phases were separated, the aqueous phase was discarded, and the organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to give 3- [3, 3, 3-tridedeuterium-2-nitro-2- (trideuteromethyl) propyl ester as a yellow oil]Tetrahydropyran-2-one (41.8g, 98%). this material was used in the next step without further purification. ESI-MS M/z calculated 207.22, Experimental 208.10(M +1)⁺(ii) a Retention time: 3.29min (LC method Q).

Step 2: 3- (3-hydroxypropyl) -5, 5-bis (Trideuteromethyl) pyrrolidin-2-one

A slurry of Raney nickel (5g, 85mmol) in water (10mL) was added to 3- [3, 3, 3-Trideuterium-2-nitro-2- (Trideuteromethyl) propyl]Tetrahydropyran-2-one (41.8g, 201.8mmol) in ethanol (600mL) at 60PSI H ₂The resulting slurry was hydrogenated at 80 ℃ for 22h, cooled to room temperature, filtered through celite, and then concentrated in vacuo to give an orange oilThe orange oil was purified by silica gel chromatography (0% -50% ethyl acetate/hexanes gradient) to give pure 3- (3-hydroxypropyl) -5, 5-bis (trideuteromethyl) pyrrolidin-2-one (7g, 20%) as an off-white solid.¹H NMR (250MHz, dimethylsulfoxide-d)₆)7.62(s, 1H), 4.39(t, 1H), 3.81(M, 2H), 2.37(M, 2H), 2.01(dd, 1H), 1.73(M, 1H), 1.43(M, 3H), 1.17(M, 1H). ESI-MS M/z calculated 177.20, Experimental 178.00(M +1)⁺(ii) a Retention time: 1.91min (LC method Q).

And step 3: (3S) -3- (3-hydroxypropyl) -5, 5-bis (Trideuteromethyl) pyrrolidin-2-one

Racemic 3- (3-hydroxypropyl) -5, 5-bis (trideuteromethyl) pyrrolidin-2-one (6.78g) was subjected to chiral separation by SFC chromatography using ChiralPak IA (250 × 21.2mm column, 5 μm particle size) and 10% methanol (no modifier)/90% carbon dioxide mobile phase (70mL/min over 7.0min) (injection volume 500 μ L of 32 mg/mL solution in methanol) to give (3S) -3- (3-hydroxypropyl) -5, 5-bis (trideuteromethyl) pyrrolidin-2-one (2.4g, 70.7%) as the first enantiomer to be eluted as an off-white solid. ESI-MS M/z calculated 177.20, Experimental 178.00(M +1) ⁺(ii) a Retention time: 1.91min (LC method B).

And 4, step 4: 3- [ (3S) -5, 5-bis (Trideuteromethyl) pyrrolidin-3-yl ] propan-1-ol

To a suspension of lithium aluminum hydride (1.37g, 35.16mmol) (2 pellets) in tetrahydrofuran (22mL) was added solid (3S) -3- (3-hydroxypropyl) -5, 5-bis (trideuteromethyl) pyrrolidin-2-one (2.4g, 13.54mmol) portionwise at room temperature over 20min under nitrogen atmosphere. The internal temperature was maintained below 32 ℃ during the addition. The reaction was then heated to reflux and stirred under a nitrogen atmosphere after 19h, the reaction became thick and no more stirred, the reaction was cooled to room temperature, andtetrahydrofuran (10mL) and methyl tert-butyl ether (10mL) were added to the mixture followed by dropwise addition of saturated sodium sulfate (aq.) until no more bubbles formed. Another 10mL saturated solution of sodium sulfate was added to the cloudy solution]Propan-1-ol (1.85g, 83%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)4.32(t，J＝5.2Hz，1H)，3.36 (q，J＝6.2Hz，3H)，2.95(dd，J＝10.6，7.5Hz，1H)，2.40(dd，J＝10.6，7.6Hz，1H)， 2.03(hept，J＝7.7Hz，1H)，1.86(m，1H)，1.68(dd，J＝12.1，8.2Hz，1H)，1.47-1.22 (m，5H)，1.01(dd，J＝12.1，8.8Hz，1H).

And 5: (4S) -4- (3-hydroxypropyl) -2, 2-bis (Trideuteromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester

To 3- [ (3S) -5, 5-bis (Trideuteromethyl) pyrrolidin-3-yl group ]To a solution of propan-1-ol (1.85g, 11.33mmol) (1.85g) in methyl t-butyl ether (11.5mL) was added tert-butyl carbonoyl formate (2.60g, 11.91 mmol). The reaction was stirred at room temperature under a nitrogen atmosphere. After 17h, the reaction was diluted with water and extracted the aqueous layer was re-extracted with methyl tert-butyl ether. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to provide a clear oil (2.94 g). The clear oil was purified by flash chromatography (silica, 30% ethyl acetate/hexanes) to provide tert-butyl (4S) -4- (3-hydroxypropyl) -2, 2-bis (trideuteromethyl) pyrrolidine-1-carboxylate (2.41g, 81%) as a clear oil.¹H NMR (400MHz, dimethylsulfoxide-d)₆)4.36(t，J＝5.2Hz，1H)， 3.61-3.48(m，1H)，3.37(q，J＝6.0Hz，2H)，2.76(q，J＝10.1Hz，1H)，2.14-1.96(m， 1H)，1.95-1.77(m，1H)，1.48-1.24(m，14H)。

Step 6: (4S) -4- (3-Methylsulfonyloxypropyl) -2, 2-bis (Trideuteromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl (4S) -4- (3-hydroxypropyl) -2, 2-bis (Trideuteromethyl) pyrrolidine-1-carboxylate (2.41g, 9.149mmol) in methyl tert-butyl ether (15mL) was added triethylamine (1.111 g, 1.530mL, 10.98mmol) followed by methanesulfonyl chloride (781. mu.L, 10.09mmol) over 5min in an ice-water bath, whereupon a white precipitate formed. The reaction mixture was allowed to reach room temperature then diluted with methyl tert-butyl ether, filtered, washed with water, dried over sodium sulfate, filtered and concentrated after standing overnight, (4S) -4- (3-methylsulfonyloxypropyl) -2, 2-bis (trideuteriomethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (2.64g, 81%) solidified to a white solid. ¹H NMR (400MHz, dimethylsulfoxide-d)₆)4.19(t，J＝6.4Hz，2H)，3.63-3.50(m， 1H)，3.16(s，3H)，2.79(q，J＝10.3Hz，1H)，2.17-2.02(m，1H)，1.97-1.80(m，1H)， 1.73-1.58(m，2H)，1.47-1.26(m，12H)。

And 7: (4S) -4- (3-azidopropyl) -2, 2-bis (Trideuteromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl (4S) -4- (3-methylsulfonyloxypropyl) -2, 2-bis (trideuteriomethyl) pyrrolidine-1-carboxylate (2.64g, 7.576mmol) in N, N-dimethylformamide (26mL) was added sodium azide (1.07g, 16.46mmol) at room temperature. The reaction was heated to 50 ℃ and stirred under a nitrogen atmosphere. The reaction was cooled to room temperature and extracted with ethyl acetate (200mL) and washed with water (50 mL.) the organic layer was dried over sodium sulfate, filtered and concentrated heptane was added and concentrated to remove any excess N, N-dimethylformamide to give (4S) -4- (3-azidopropyl) -2, 2-bis (trideuteriomethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (1.77g, 80.2%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)3.55(dt，J＝10.7，7.1Hz，1H)，3.32(t， 2H)，2.85-2.70(m，1H)，2.20-2.01(m，1H)，1.88(td，J＝14.0，13.5，6.1Hz，1H)， 1.61-1.28(m，14H)。

And 8: (4S) -4- (3-aminopropyl) -2, 2-bis (Trideuteromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of (4S) -4- (3-azidopropyl) -2, 2-bis (Trideuteromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (1.77g, 6.137mmol) in ethyl acetate (330.8mL) was added platinum oxide (50.68mg, 0.2232 mmol.) the reaction mixture was hydrogenated using a Buchilglaster hydrogenation apparatus the mixture was vacuum purged three times with nitrogen then three times with hydrogen (0.4L). The reaction was stirred at 930rpm under hydrogen atmosphere at 25 ℃ under about 2.18 bar hydrogen pressure for 18 h.337 mL of hydrogen was consumed. The reaction mixture was filtered through celite and washed with water (25 mL.) the organic layer was washed with brine (25mL), dried over sodium sulfate, filtered and concentrated to afford (4S) -4- (3-aminopropyl) -2, 2-bis (trideuteromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester as a dark oil (1.66g, quantitative yield). ¹H NMR (400MHz, dimethylsulfoxide-d)₆)3.53(dt，J＝12.2， 6.5Hz，1H)，2.76(q，J＝10.2Hz，1H)，2.18-1.99(m，1H)，1.86(td，J＝15.8，14.2， 6.1Hz，1H)，1.55-1.21(m，16H)。

And step 9: (4S) -4- [3- [ (6-sulfamoyl-2-pyridyl) amino ] propyl ] -2, 2-bis (Trideuteromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl (4S) -4- (3-aminopropyl) -2, 2-bis (trideuteriomethyl) pyrrolidine-1-carboxylate (1.61g, 6.135 mmol) in dimethyl sulfoxide (30mL) was added diisopropylethylamine (1.28mL, 7.349mmol) followed by 6-fluoropyridine-2-sulfonamide (1.31g, 7.436 mmol). The reaction was placed under a nitrogen atmosphere and stirred at 85 ℃ for 18 h. The reaction mixture was diluted with methyl tert-butyl ether (50mL) and extracted with water (20mL)The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was dissolved in dichloromethane and purified by silica gel chromatography (60% ethyl acetate/hexane). To combine the product containing fractions, a second purification was accomplished by silica gel chromatography (gradient of 0% to 5% methanol in dichloromethane) to afford (4S) -4- [3- [ (6-sulfamoyl-2-pyridyl) amino group as a white viscous solid]Propyl radical]-tert-butyl 2, 2-bis (trideuteromethyl) pyrrolidine-1-carboxylate (1.72g, 67%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)7.51(t，J＝8.5，7.2Hz，1H)， 7.06(s，2H)，7.01-6.88(m，2H)，6.61(d，J＝8.4Hz，1H)，3.55(q，J＝9.2Hz，1H)， 3.30-3.21(m，2H)，2.88-2.71(m，1H)，2.19-2.00(m，1H)，2.01-1.78(m，1H)， 1.66-1.27(m，14H)。

Step 10: (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1] hept-7-ylethoxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridyl ] amino ] propyl ] -2, 2-bis (Trideuteromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester

To 2-chloro-6- [3- (2-dispiro [2.0.2.1 ]]Hept-7-ylethoxy) pyrazol-1-yl]To a solution of pyridine-3-carboxylic acid (250mg, 0.6892mmol) in tetrahydrofuran (2.058mL) was added carbonyldiimidazole (134mg, 0.8264 mmol). The reaction was stirred at room temperature for 30min carbonyl diimidazole (11.8mg, 0.07277mmol) was added and it was stirred for a further 30min. (4S) -4- [3- [ (6-sulfamoyl-2-pyridyl) amino) propyl ] is added dropwise]-2, 2-bis (Trideuteromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (307mg, 0.7334mmol) in tetrahydrofuran (420 μ L) followed by addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (310 μ L, 2.073 mmol.) the reaction was stirred further at room temperature under nitrogen. After 18h, water (8.2mL), ethyl acetate (25mL) and hydrochloric acid (710 μ L, 6M, 4.260mmol) were added to bring the pH to 3 in the aqueous layer the reaction mixture was extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated purification was performed by flash chromatography (50% ethyl acetate/hexanes) to afford (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1 ])]G-channel wine7-ylethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-tert-butyl 2, 2-bis (trideuteromethyl) pyrrolidine-1-carboxylate (308mg, 59%). ESI-MS M/z calculated 759.35, Experimental 760.4(M +1) ⁺(ii) a Retention time: 2.20min (LC method G).

Step 11: n- [ [6- [3- [ (3S) -5, 5-bis (Trideuteromethyl) pyrrolidin-3-yl ] propylamino ] -2-pyridyl ] sulfonyl ] -2-chloro-6- [3- (2-dispiro [2.0.2.1] hept-7-ylethoxy) pyrazol-1-yl ] pyridine-3-carboxamide

To (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-bis (Trideuteromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (308 mg, 0.3565mmol) in dichloromethane (1.26mL) and toluene (624 μ L) trifluoroacetic acid (411 μ L, 5.335mmol) was added and the mixture stirred at ambient temperature for 2.5h the reaction mixture was concentrated, diluted with toluene (4.989mL) and concentrated at 45 ℃ to give N- [ [6- [3- [ (3S) -5, 5-bis (Trideuteromethyl) pyrrolidin-3-yl]Propylamino group]-2-pyridyl]Sulfonyl radical]-2-chloro-6- [3- (2-dispiro [2.0.2.1]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carboxamide (trifluoroacetate) (276mg, 100%). ESI-MS M/z calcd for 659.2928, experimental value 660.4(M +1)⁺(ii) a Retention time: 1.11min (LC method G).

Step 12: (14S) -8- [3- (2- { dispiro [2.0.2.1]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl ]-12, 12-bis (trideuterio) methyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 274)

To N- [ [6- [3- [ (3S) -5, 5-bis (Trideuteromethyl) pyrrolidin-3-yl group]Propylamino group]-2-pyridyl]Sulfonyl radicalBase of]-2-chloro-6- [3- (2-dispiro [2.0.2.1 ]]Hept-7-ylethoxy) pyrazol-1-yl]To a solution of pyridine-3-carboxamide (trifluoroacetate) (356mg, 0.4598mmol) in NMP (8.6mL) was added potassium carbonate (322mg, 2.330 mmol). The mixture was purged 3 times with nitrogen and heated at 150 ℃ overnight the reaction mixture was cooled to room temperature and added to water (18 mL). The mixture was carefully acidified with hydrochloric acid (5mL, 1M, 5.000mmol) to give a multivesicular slurry the solid was collected by filtration using a medium pore glass frit. The filtrate is free of product and is discarded. The wet cake was dissolved in ethyl acetate (21mL) and washed with 10mL brine. The aqueous phase was separated and the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to give a light yellow oil. The crude product was diluted with acetonitrile and subjected to 30g of reverse phase C₁₈Performing column chromatography, and eluting with 60% -100% acetonitrile/water gradient to obtain (14S) -8- [3- (2- { dispiro [2.0.2.1 ] as milk yellow foam ]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-bis (trideuterio) methyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 274) (135mg, 47%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.50(s, 1H), 8.20(d, J ═ 2.8Hz, 1H), 7.81(d, J ═ 8.2Hz, 1H), 7.57 (t, J ═ 7.8Hz, 1H), 7.19-6.81(M, 3H), 6.71(d, J ═ 8.5Hz, 1H), 6.08(d, J ═ 2.8Hz, 1H), 4.21(t, J ═ 6.7, 1.4Hz, 2H), 4.08-3.81(M, 1H), 3.24-3.03(M, 1H), 2.95(d, J ═ 13.3Hz, 1H), 2.80-2.57(M, 1H), 2.18(d, J ═ 50.0, 1H), 1.97-1.68(M, 68H), 1.42H, 1.42(M, 42H), 2.42-2.42 (M, 1H), 2.18 (M, 1H), 2.18 (M, 31H, 31H), 5H, 31H, 5M, 11M, 5M, 3H, M.⁺(ii) a Retention time: 1.98min (LC method G).

Example 94: preparation of 20, 20, 22-trimethyl-4- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl]-10λ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docodeca-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (rac atropisomer 1) (compound 280), 12, 20, 20-trimethyl-4- [3- (3, 3, 3-trifluoro-2, 2- Dimethylpropoxy) -1H-pyrazol-1-yl]-10λ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (compound 281) and 20, 20, 22-trimethyl-4- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl]-10λ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (rac atropisomer 2) (compound 282)

Step 1: 2, 2-dimethyl-4- [3- (5-methyl-4-sulfamoyl-pyrazol-1-yl) propyl ] pyrrolidine-1-carboxylic acid tert-butyl ester and 2, 2-dimethyl-4- [3- (3-methyl-4-sulfamoyl-pyrazol-1-yl) propyl ] pyrrolidine-1-carboxylic acid tert-butyl ester (2: 1 mixture of inseparable regioisomers)

To a round-bottomed flask containing tert-butyl 2, 2-dimethyl-4- (3-methylsulfonyloxypropyl) pyrrolidine-1-carboxylate (1.97g, 5.873mmol) were added N, N-dimethylformamide (20mL), potassium carbonate (2.44g, 17.65 mmol) and 5-methyl-1H-pyrazole-4-sulfonamide (947mg, 5.875 mmol). The reaction was heated at 65 ℃ for 24 h. The reaction was filtered and the flask and filter cake were further washed with ethyl acetate the filtrate was evaporated and purified by HPLC (20% to 80% acetonitrile/water gradient and 0.1% hydrochloric acid modifier) the purified fractions were evaporated together to provide a white foam. By passing ¹H NMR analysis confirmed the inseparable regioisomeric product 2, 2-dimethyl-4- [3- (5-methyl-4-sulfamoyl-pyrazol-1-yl) propyl]Pyrrolidine-1-carboxylic acid tert-butyl ester and 2, 2-dimethyl-4- [3- (3-methyl) ethyl ester-4-sulfamoyl-pyrazol-1-yl) propyl]Pyrrolidine-1-carboxylic acid tert-butyl ester (972mg combined yield, 41%), ESI-MS M/z calculated 400.21442, experimental 345.2(M +1)⁺(ii) a Retention time: 1.51min (LC method B) was present in the product mixture in a 2: 1 ratio.

Step 2: 4- [3- [4- [ [ 2-chloro-6- [3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -5-methyl-pyrazol-1-yl ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 4- [3- [4- [ [ 2-chloro-6- [3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -3-methyl-pyrazol-1-yl ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2: 1 mixture of inseparable regioisomers)

Adding 2-chloro-6- [3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) pyrazol-1-yl to a round bottom flask]Pyridine-3-carboxylic acid (952mg, 2.565mmol), carbonyldiimidazole (469mg, 2.892mmol) and tetrahydrofuran (10 mL). The reaction was heated at 35 ℃ and stirred for 2h, 2-dimethyl-4- [3- (5-methyl-4-sulfamoyl-pyrazol-1-yl) propyl ] was added ]Pyrrolidine-1-carboxylic acid tert-butyl ester and 2, 2-dimethyl-4- [3- (3-methyl-4-sulfamoyl-pyrazol-1-yl) propyl ester]A 2: 1 mixture of pyrrolidine-1-carboxylic acid tert-butyl ester (965mg, 2.409mmol) and 1, 8-diazabicyclo [5.4.0]Undec-7-ene (1.10mL, 7.356mmol) and the reaction was stirred at room temperature overnight. The reaction was directly purified by silica gel chromatography using a gradient of 20% to 100% ethyl acetate/hexane. The inseparable regioisomeric product 4- [3- [4- [ [ 2-chloro-6- [3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-5-methyl-pyrazol-1-yl]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 4- [3- [4- [ [ 2-chloro-6- [3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-3-methyl-pyrazol-1-yl]Propyl radical]Isolation of tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (1.073g combined yield, 60%) as a white foam ESI-MS m/bambooz calculated 745.2636, Experimental value 746.4(M +1)⁺(ii) a Retention time: 1.85min (LC method G). By passing¹H NMR confirmed the regiochemical ratio of the mixture (2: 1).

And step 3: 2-chloro-N- [1- [3- (5, 5-dimethylpyrrolidin-3-yl) propyl ] -5-methyl-pyrazol-4-yl ] sulfonyl-6- [3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) pyrazol-1-yl ] pyridine-3-carboxamide and 2-chloro-N- [1- [3- (5, 5-dimethylpyrrolidin-3-yl) propyl ] -3-methyl-pyrazol-4-yl ] sulfonyl-6- [3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) pyrazol-1-yl ] pyridine-3-carboxamide (inseparable regioisomers of 2: 1 mixture)

To a solution containing 4- [3- [4- [ [ 2-chloro-6- [3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-5-methyl-pyrazol-1-yl]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 4- [3- [4- [ [ 2-chloro-6- [3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-3-methyl-pyrazol-1-yl]Propyl radical]A round-bottomed flask of a 2: 1 mixture of tert-butyl (E) -2, 2-dimethyl-pyrrolidine-1-carboxylate (1.068 g, 1.431mmol) was charged with dichloromethane (15mL) and trifluoroacetic acid (4.4mL, 57.11 mmol). The reaction was stirred at rt for 1 h. The aqueous layer was evaporated to dryness and anhydrous acetone was added to the solid and filtered to evaporate acetone solute and combined with the organic layer to provide 2-chloro-N- [1- [3- (5, 5-dimethylpyrrolidin-3-yl) propyl ] acetate]-5-methyl-pyrazol-4-yl]Sulfonyl-6- [3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) pyrazol-1-yl]Pyridine-3-carboxamide and 2-chloro-N- [1-3- (5, 5-dimethylpyrrolidin-3-yl) propyl ]-3-methyl-pyrazol-4-yl]Sulfonyl-6- [3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) pyrazol-1-yl]Pyridine-3-carboxamides (2: 1 mixture of inseparable regioisomers)Compound) (920mg, 100%). ESI-MS M/z calculated 645.2112, Experimental value 646.3(M +1)⁺(ii) a Retention time: 1.45min (LC method B).

And 4, step 4: 20, 20, 22-trimethyl-4- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl]-10λ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (rac atropisomer 1) (compound 280), 12, 20, 20-trimethyl-4- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl]-10λ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (compound 281) and 20, 20, 22-trimethyl-4- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl]-10λ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (rac atropisomer 2) (compound 282)

To a 250mL round bottom flask was added cesium fluoride (432mg, 2.844mmol), potassium carbonate (984mg, 7.120mmol),

Molecular sieves and regioisomers (2-chloro-N- [1- [3- (5, 5-dimethylpyrrolidin-3-yl) propyl)]-5-methyl-pyrazol-4-yl]Sulfonyl-6- [3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) pyrazol-1-yl]Pyridine-3-carboxamide and 2-chloro-N- [1-3- (5, 5-dimethylpyrrolidin-3-yl) propyl]-3-methyl-pyrazol-4-yl]Sulfonyl-6- [3- (3, 3, 3-trifluoro-2, 2-dimethyl-propoxy) pyrazol-1-yl]Pyridine-3-carboxamide) (2: 1 mixture of inseparable regioisomers) (920mg, 1.424mmol) in dimethylsulfoxide (55mL) the reaction was purged with nitrogen and heated at 150 ℃ overnight, the reaction was cooled to room temperature, filtered, washed with brine and extracted with ethyl acetate. Will haveThe organic layer was dried over sodium sulfate, filtered and purified by HPLC (10% -70% acetonitrile/water + 0.1% hydrochloric acid modifier) to provide 20, 20, 22-trimethyl-4- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl as the first atropisomer/regioisomer to be eluted]-10λ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7 ]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (rac atropisomer 1) (compound 280) (45mg, 10%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.41(s, 1H), 8.19(d, J ═ 2.8Hz, 1H), 7.86(s, 1H), 7.77(d, J ═ 8.2Hz, 1H), 6.93(d, J ═ 8.2Hz, 1H), 6.16(d, J ═ 2.8Hz, 1H), 4.38(d, J ═ 14.2Hz, 1H), 4.23(s, 2H), 4.01(t, J ═ 13.7Hz, 1H), 2.05(s, 3H), 1.89-1.70(M, 3H), 1.55(s, 3H), 1.48(s, 3H), 1.44-1.28(M, 2H), 1.23(s, 6H), 1.08 (d, J ═ 11.1Hz, 1H), 1H, ESI, 610.4 (calculated values of M + z)⁺(ii) a Retention time: 3.01min (LC method D). The second atropisomer/regioisomer to be eluted was 12, 20, 20-trimethyl-4- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl]-10λ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (Compound 281) (73mg, 17%). ESI-MS M/z calculated 609.2345, Experimental value 610.4(M +1)⁺(ii) a Retention time: 3.07min (LC method D). The third atropisomer/regioisomer to be eluted was 20, 20, 20-trimethyl-4- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl ]-10λ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (rac atropisomer 2) (compound 282) (19mg, 4%). ESI-MS M/z calculated 609.2345, Experimental value 610.4(M +1)⁺(ii) a Retention time: 3.14min (LC method D).

Example 95: preparation of (14S) -8- (3- { 2-hydroxy-3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) -12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5(10), 6, 8, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 284) and (14S) -8- (3- { 2-hydroxy-3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) -12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5(10), 6, 8, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 283)

Step 1: (14S) -8- (3- { 2-hydroxy-3- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Propoxy } -1H-pyrazol-1-yl) -12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosane-1 (22), 5(10), 6, 8, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 284) and (14S) -8- (3- { 2-hydroxy-3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) -12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5(10), 6, 8, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 283)

(14S) -8- (3- { 2-hydroxy-3- [1- (trifluoromethyl) cyclopropyl) amino acid sequence by SFC chromatography using a ChiralPak IG column (250X 10mm, 5 μm particle size) and a mobile phase of 44% acetonitrile/methanol (90: 10)/56% carbon dioxide (10mL/min over 12.0min)]Propoxy } -1H-pyrazol-1-yl) -12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5(10), 6, 8, 19(23), 20-hexaen-2, 2, 4-trione (3.24g, 8.383mmol) was subjected to chiral separation (injection volume: 70 μ L of a solution of 22mg/mL in acetonitrile/methanol (90: 10)) to give (14S) -8- (3- { 2-hydroxy-3) as a white solid of the first diastereomer to be eluted- [1- (trifluoromethyl) cyclopropyl group]Propoxy } -1H-pyrazol-1-yl) -12, 12-dimethyl-2 lambda ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5(10), 6, 8, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 284) (6.8mg, 49%);¹h NMR (400MHz, dimethylsulfoxide-d)₆)12.52(s, 1H), 8.22(d, J ═ 2.8Hz, 1H), 7.82(d, J ═ 8.2Hz, 1H), 7.57(t, J ═ 7.9Hz, 1H), 7.05(d, J ═ 7.2Hz, 1H), 6.98(s, 1H), 6.92(d, J ═ 8.2Hz, 1H), 6.71(d, J ═ 8.5Hz, 1H), 6.13(d, J ═ 2.8Hz, 1H), 5.07(d, J ═ 5.7Hz, 1H), 4.10(d, J ═ 5.2Hz, 2H), 4.00-3.72(m, 2H), 3.16(s, 1H), 2.95(d, J ═ 13.5, 1H), 1.68 (d, J ═ 2H), 1.68(s, 2H), 1H), 1.67 (s, 1H), 2.67 (d, 1H), 2.6.6.6.6.6 (d, J ═ 2.8H, 1H), 3H) 1.57(d, J ═ 12.6Hz, 2H), 1.52(s, 3H), 1.33(t, J ═ 12.0Hz, 1H), 1.05-0.90 (m, 2H), 0.90-0.70(m, 2H); ESI-MS M/z calculated 663.24506, Experimental 664.4 (M +1)⁺(ii) a Retention time: 1.9min (LC method E). And (14S) -8- (3- { 2-hydroxy-3- [1- (trifluoromethyl) cyclopropyl ] as a white solid of the second diastereomer to be eluted ]Propoxy } -1H-pyrazol-1-yl) -12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5(10), 6, 8, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 283) (7.62 mg, 54%);¹h NMR (400MHz, dimethylsulfoxide-d)₆)12.52(s，1H)，8.22(d，J＝2.8Hz， 1H)，7.82(d，J＝8.2Hz，1H)，7.58(t，J＝7.9Hz，1H)，7.06(d，J＝7.2Hz，1H)，7.04- 6.94(m，1H)，6.92(d，J＝8.2Hz，1H)，6.71(d，J＝8.5Hz，1H)，6.14(d，J＝2.7Hz， 1H)，4.14-4.06(m，2H)，3.96(dp，J＝15.9，6.0，5.0Hz，2H)，3.16(s，1H)，2.95(d，J ＝13.3Hz，1H)，2.70(d，J＝11.1Hz，1H)，2.50-2.36(m，1H)，2.13(s，1H)，1.98(dd， J＝15.0，4.0Hz，1H)，1.86(dd，J＝11.8，5.2Hz，1H)，1.77(s，1H)，1.71-1.65(m， 1H)，1.63(s，1H)，1.61(s，3H)，1.57(d, J ═ 12.3Hz, 2H), 1.52(s, 3H), 1.31(q, J ═ 13.6, 12.7Hz, 1H), 1.04-0.91(m, 2H), 0.90-0.77(m, 2H); ESI-MS calculated M/z 663.24506, Experimental 664.4(M +1) +; retention time: 1.9min (LC method E).

Example 96: preparation of (14S) -12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl]-2, 2, 3, 3-tetradeuterium-propoxy } -1H-pyrazol-1-yl) -2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (Compound 287)

Step 1: 1, 1, 2, 2-tetradeuterium-2- [1- (trifluoromethyl) cyclopropyl ] ethanol

To a suspension of lithium aluminum deuteride (1.0872g, 27.204mmol) in anhydrous tetrahydrofuran (50mL) at 0 deg.C was added 2, 2-dideutero-2- [1- (trifluoromethyl) cyclopropyl]A solution of acetic acid (4g, 20.926mmol) in dry tetrahydrofuran (50mL) the reaction mixture was stirred at room temperature for 16h, the reaction was diluted with diethyl ether (50mL) and cooled to 0 deg.C, and then quenched with water (1.1mL), 15% sodium hydroxide (aq, 1.1mL), and water (3.3mL) in that order. The reaction was stirred at room temperature for 30min and then filtered through a pad of celite and dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 1, 1, 2, 2-tetradeuterium-2- [1- (trifluoromethyl) cyclopropyl ] as a clear liquid ]Ethanol (3.288g, 92%).¹H NMR(250MHz，CDCl₃) 1.42(s，1H)，1.03-0.89(m，2H)，0.67(m，2H).

Step 2: [1, 1, 2, 2-Tetradeuterium-2- [1- (trifluoromethyl) cyclopropyl ] ethyl ] methanesulfonate

To 1, 1, 2, 2-tetradeuterium-2- [1- (trifluoromethyl) cyclopropyl group at 0 deg.C]Ethanol (3.288g, 19.334mmol) and triethylamine (5.8692g, 8.0843mL, 58.002mmol) in dichloromethane (35mL) was added dropwise methanesulfonyl chloride (2.6577g, 1.7957mL, 23.201mmol) to a solution of dichloromethane (35mL) the reaction mixture was stirred at room temperature for 1h and then diluted with dichloromethane (50mL) and 10% citric acid (50mL) the two layers were separated and the organic layer was washed with saturated sodium bicarbonate (50mL) and brine (50mL), the organic solution was dried over anhydrous sodium sulfate and concentrated in vacuo the residue was purified by silica gel chromatography using a gradient of 0% to 70% diethyl ether/hexane to give [1, 1, 2, 2-tetradeuterium-2- [1- (trifluoromethyl) cyclopropyl ] column as a clear liquid]Ethyl radical]Methane sulfonate (3.982g, 83%).¹H NMR(250MHz，CDCl₃)3.01(s，3H)，1.03(m，2H)，0.71(m，2H).

And step 3: 2, 2, 3, 3-tetradeuterium-3- [1- (trifluoromethyl) cyclopropyl ] propionitrile

To [1, 1, 2, 2-tetradeuterium-2- [1- (trifluoromethyl) cyclopropyl group]Ethyl radical]To a solution of methanesulfonate (3.982g, 16.013 mmol) in dimethyl sulfoxide (20mL) was added sodium cyanide (980.93mg, 20.016 mmol). The reaction mixture was stirred at 70 ℃ for 2 days, cooled to room temperature, poured into water (50mL) and the aqueous solution was extracted with diethyl ether (3X 50 mL). The combined organic layers were washed with water (2X 50mL) and brine (50mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 2, 2, 3, 3-tetradeuterium-3- [1- (trifluoromethyl) cyclopropyl ] as a pale yellow oil ]Propionitrile (2.769g, 96%).¹H NMR(250MHz，CDCl₃) 1.12-1.00(m，2H)，0.78-0.66(m，2H).

And 4, step 4: 2, 2, 3, 3-tetradeuterium-3- [1- (trifluoromethyl) cyclopropyl ] propionic acid

To the 2, 2, 3, 3-tetradeuterium-3- [1- (trifluoromethyl) cyclopropyl group]Propionitrile (2.769g, 15.405mmol) in CH₃To a solution in Cwater D (30mL) was added sodium deuteroxide (6.3166g, 40% w/w, 61.620 mmol) and deuterium oxide (6 mL). The reaction mixture was stirred at 70 ℃ for 16h. The aqueous phase was acidified to pH about 1 and extracted with diethyl ether (3X 50 mL.) the combined ether layers were washed with brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2, 2, 3, 3-tetradeuterium-3- [1- (trifluoromethyl) cyclopropyl ] as a yellow liquid]Propionic acid (2.737g, 91%).¹H NMR(250MHz，CDCl₃) 1.08-0.83(m，2H)，0.72-0.49(m，2H)。

And 5: 2, 2, 3, 3-tetradeuterium-3- [1- (trifluoromethyl) cyclopropyl ] propan-1-ol

To a suspension of lithium aluminum hydride (689.14mg, 0.7515mL, 18.157mmol) in anhydrous tetrahydrofuran (20mL) at 0 deg.C was added 2, 2, 3, 3-tetradeuterium-3- [1- (trifluoromethyl) cyclopropyl ] dropwise]A solution of propionic acid (2.737g, 13.967mmol) in anhydrous tetrahydrofuran (20 mL). The reaction was stirred at rt for 16h. The reaction mixture was diluted with diethyl ether (20mL) and cooled to 0 ℃. Water (0.7mL), 15% sodium hydroxide (aq) (0.7mL), and water (2.1mL) were added in that order. The reaction mixture was stirred at room temperature for 30min and filtered through a pad of celite the filtrate was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 2, 2, 3, 3-tetradeuterium-3- [1- (trifluoromethyl) cyclopropyl group as a clear liquid ]Propan-1-ol (2.04g, 84%).¹H NMR (250MHz, dimethylsulfoxide-d)₆)4.44(t，J＝5.1Hz，1H)，3.38(s，2H)，0.95-0.79(m，2H)，0.68(dd，J＝2.2， 1.2Hz，2H).

Step 6: 3- [2, 2, 3, 3-Tetradeuterium-3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazole-1-carboxylic acid tert-butyl ester

To 5-oxo-1H-pyrazole-2-carboxylic acid tert-butyl ester (2.08g, 11.29mmol) and 2, 2, 3, 3-tetradeuterium-3- [1- (trifluoromethyl) cyclopropyl]To a solution of propan-1-ol (2.04g, 11.85mmol) in tetrahydrofuran (26mL) was added triphenylphosphine (3.108g, 11.85mmol). to the mixture was added slowly dropwise diisopropyl azodicarboxylate (2.396g, 11.85mmol) over 10min (note exotherm). The reaction mixture was stirred at room temperature for 2 h. Tetrahydrofuran was removed in vacuo toluene (16.64mL) was added to the crude reaction mixture and the mixture was stirred overnight. The solution was concentrated in vacuo and the crude product was purified by silica gel chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate to give 3- [2, 2, 3, 3-tetradeuterium-3- [1- (trifluoromethyl) cyclopropyl ] as a clear slurry]Propoxy group]Pyrazole-1-carboxylic acid tert-butyl ester (2.43g, 64%). ESI-MS M/z calculated 338.17554, Experimental 339.0 (M +1)⁺(ii) a Retention time: 0.75min (LC method A).

And 7: 3- [2, 2, 3, 3-tetradeuterium-3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] -1H-pyrazole

3- [2, 2, 3, 3-tetradeuterium-3- [1- (trifluoromethyl) cyclopropyl group]Propoxy group]Pyrazole-1-carboxylic acid tert-butyl ester (2.43g, 7.182mmol) was dissolved in dichloromethane (24.3mL) and trifluoroacetic acid (8.297mL, 107.7mmol) and the reaction was stirred at room temperature for 120min]Propoxy group]-1H-pyrazole (1.711g, 100%). ESI-MS M/z calculated 238.12311, Experimental 239.1(M +1)⁺(ii) a Retention time: 0.54min (LC method A).

And 8: 2-chloro-6- [3- [2, 2, 3, 3-tetradeuterium-3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carboxylic acid tert-butyl ester

2, 6-dichloropyridine-3-carboxylic acid tert-butyl ester (1.782g, 7.182mmol), 3- [2, 2, 3, 3-tetradeuterium-3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]-1H-pyrazole (1.711g, 7.182mmol) and potassium carbonate (1.192g, 8.625 mmol) in anhydrous dimethylsulfoxide (34.22 mL.) 1, 4-diazabicyclo [2.2.2 ] was added ]Octane (161.3 mg, 1.438mmol) and the mixture was stirred at room temperature under nitrogen for 16h the reaction mixture was diluted with water (65.81mL) and stirred for 15 min. The resulting white solid was filtered and washed with water the solid was dissolved in dichloromethane and dried over magnesium sulfate the mixture was filtered and the filtrate was evaporated to give 2-chloro-6- [3- [2, 2, 3, 3-tetradeuterium-3- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (2.58g, 80%). ESI-MS M/z calculated 449.16312, Experimental value 450.0(M +1)⁺(ii) a Retention time: 0.91min (LC method A).

2-chloro-6- [3- [2, 2, 3, 3-tetradeuterium-3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (2.58g, 5.735mmol) was dissolved in dichloromethane (25.8mL) and trifluoroacetic acid (6.627mL, 86.02mmol) and the reaction was stirred at room temperature for 16h. Trifluoroacetic acid (2.209mL, 28.67mmol) was added and stirring was continued for 30min. This was repeated two more times, yielding a white solid that was recrystallized from dichloromethane to give the pure product (crop)1) as a solid. The product remaining in the filtrate, evaporating the filtrate to give an off-white solid, which is then solidified The body was dissolved in ethyl acetate and washed with 5N sodium hydroxide (2 ×), followed by 1N hydrochloric acid (1 ×), then dried (sodium sulfate), filtered and concentrated to a white solid which was purified by silica gel chromatography using a gentle gradient of 100% dichloromethane to 20% methanol/dichloromethane resulting in poor separation₁₈(2) Column (75 × 30mM, 5 μm particle size) (pn: 00C-4252-U0-AX) and dual gradient run of 20% -80% mobile phase B over 15.0min (mobile phase a ═ water (5mM hydrochloric acid), mobile phase B ═ acetonitrile, flow rate 50mL/min, injection volume 950 μ L and column temperature 25 ℃) to give pure product material, which was combined with the original crystalline solid material to give 2-chloro-6- [3- [2, 2, 3, 3-tetradeuterium-3- [1- (trifluoromethyl) cyclopropyl as a white solid]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxylic acid (1.75g, 78%). ESI-MS M/z calculated 393.10052, Experimental 394.0(M +1)⁺(ii) a Retention time: 0.72min (LC method A).

Step 10: (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [2, 2, 3, 3-tetradeuterium-3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To 2-chloro-6- [3- [2, 2, 3, 3-tetradeuterium-3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxylic acid (1g, 2.539mmol) in tetrahydrofuran (6.832mL) carbonyl diimidazole (514.7 mg, 3.174mmol) was added (recrystallized from tetrahydrofuran) and the mixture was stirred at room temperature for 3h, followed by addition of (4S) -2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino group as a solution in tetrahydrofuran (2.5mL)]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (1.047g, 2.538mmol) and subsequent addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (1.192mL, 7.971mmol) and the resulting mixture was stirred at room temperature for 6 h. The reaction was diluted with water and ethyl acetate, then addedHydrochloric acid (1.418mL, 12M, 17.02mmol), followed by bringing the pH of the aqueous layer to 1. The layers were separated and the organic layer was washed with water (1 ×) and brine (1 ×), then dried over sodium sulfate, filtered and concentrated to a white foam which was subjected to 275g C₁₈Purifying with reverse phase column, eluting with 50% -100% acetonitrile/water gradient to obtain white solid (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [2, 2, 3, 3-tetradeuterium-3- [1- (trifluoromethyl) cyclopropyl)]Propoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl ]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.261g, 63%). ESI-MS M/z calculated 787.3044, Experimental 788.2(M +1)⁺(ii) a Retention time: 0.89min (LC method A).

Step 11: 2-chloro-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] propylamino ] -2-pyridinyl ] sulfonyl ] -6- [3- [2, 2, 3, 3-tetradeuterium-3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carboxamide (trifluoroacetate)

Reacting (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [2, 2, 3, 3-tetradeuterium-3- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Propoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.409g, 1.787mmol) was dissolved in dichloromethane (6.147mL) and trifluoroacetic acid (5.509mL, 71.51mmol) was added to the mixture and the mixture was stirred at room temperature for 90 min. The mixture was concentrated to dryness under reduced pressure, 50mL of toluene were added and removed by rotary evaporation (45 ℃ water bath). 50mL of toluene were again added and removed by rotary evaporation (45 ℃ water bath) followed by vacuum drying to give 2-chloro-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] as a white solid ]Propylamino group]-2-pyridyl]Sulfonyl radical]-6- [3- [2, 2, 3, 3-tetradeuterium-3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxamide (trifluoroacetate) (1.434g, 100%). ESI-MS M/z calculated 687.25195, Experimental 688.2 (M +1)⁺(ii) a Retention time: 0.62min (LC method A).

Step 12: (14S) -12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl ] methyl ester]-2, 2, 3, 3-tetradeuterium-propoxy } -1H-pyrazol-1-yl) -2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (Compound 287)

To 2-chloro-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] group]Propylamino group]-2-pyridyl]Sulfonyl radical]-6- [3- [2, 2, 3, 3-tetradeuterium-3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]To a solution of pyridine-3-carboxamide (trifluoroacetate) (1.434g, 1.788mmol) in NMP (86.04mL) was added potassium carbonate (1.73g, 12.52mmol) and the mixture was purged with nitrogen for 5 min. The mixture was subsequently heated at 155 ℃ for 18 h. The reaction mixture was cooled to room temperature and added to water (about 200mL) to give an off-white solid. The mixture was carefully acidified with hydrochloric acid (2.235mL, 12M, 26.82mmol) to give a multivesicular slurry. The wet cake was dissolved in ethyl acetate and dried over magnesium sulfate, filtered and concentrated in vacuo to give a pale yellow oil which was subjected to 275g of reverse phase C ₁₈Column chromatography, eluting with a gradient of 50% to 100% acetonitrile/water to give (14S) -12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl ] as a white solid]-2, 2, 3, 3-tetradeuterium-propoxy } -1H-pyrazol-1-yl) -2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 87) (845.2mg, 73%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.50 (s，1H)，8.21(d，J＝2.8Hz，1H)，7.81(d，J＝8.2Hz，1H)，7.58(dd，J＝8.5，7.2Hz， 1H)，7.05(d，J＝7.1Hz，1H)，6.99(s，1H)，6.91(d，J＝8.2Hz，1H)，6.71(d，J＝8.5 Hz，1H)，6.12(d，J＝2.8Hz，1H)，4.19(s，2H)，3.92(d，J＝12.2Hz，1H)，3.15(s，1H)， 2.95(d，J＝13.5Hz，1H)，2.71(s，1H)，2.12(s，1H) 1.86(dd, J ═ 11.9, 5.3Hz, 1H), 1.77(s, 1H), 1.60(s, 4H), 1.57(d, J ═ 13.9Hz, 2H), 1.51(s, 3H), 1.37-1.23(M, 1H), 0.93-0.86(M, 2H), 0.75(s, 2H), ESI-MS M/z calculated 651.27527, experimental 652.4 (M +1)⁺(ii) a Retention time: 2.25min (LC method B).

Example 97: preparation of 20, 20, 22-trimethyl-4- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl]-10λ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (atropisomer 1, enantiomer 1) (compound 288) and 20, 20, 22-trimethyl-4- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl ]-10λ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (atropisomer 1, enantiomer 2) (compound 289)

Step 1: 20, 20, 22-trimethyl-4- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl]-10λ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (atropisomer 1, enantiomer 1) (compound 288) and 20, 20, 22-trimethyl-4- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl]-10λ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (atropisomer 1, enantiomer 2) (compound 289)

Chromatography by chiral SFC using ChiralPak AS-H (250X 21.2mm column, 5 μm particle size) and 24% acetonitrile: methanol (90: 1)10; 20mM NH 3))/76% carbon dioxide mobile phase (70mL/min) to racemic 20, 20, 22-trimethyl-4- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl } -10. lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7 ]Dodecan-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (45mg, 0.07381mmol) (rac atropisomer 1) was separated to give 20, 20, 22-trimethyl-4- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl as the first enantiomer to be eluted]-10λ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (atropisomer 1, enantiomer 1) (compound 288) (18.6mg, 83%). ESI-MS M/z calculated 609.2345, experimental 610.4(M +1)⁺(ii) a Retention time: 3.0min (LC method D). the second enantiomer to be eluted was 20, 20, 22-trimethyl-4- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl]-10λ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (atropisomer 1, enantiomer 2) (compound 289) (15.5mg, 69%).¹H NMR (500MHz, dimethylsulfoxide-d)₆) 12.16(bs, 1H), 8.19(d, J ═ 2.8Hz, 1H), 7.82(s, 1H), 7.81(d, J ═ 7.9Hz, 1H), 6.92(d, J ═ 7.9Hz, 1H), 6.10(d, J ═ 2.8Hz, 1H), 4.35(M, 1H), 4.22(bs, 2H), 4.02(M, 1H), 2.53 (s, 3H), 2.02(M, 3H), 1.83(M, 2H), 1.75(dd, J ═ 12.1Hz, 5.6Hz, 1H), 1.54(s, 3H), 1.47(s, 3H), 1.36(q, J ═ 15.6Hz, 12.4, 2H), 1.22(s, 6H), 1.84 (MS, 85m, 3583M + z, calculated values (M, 2H)) ⁺(ii) a Retention time: 3.0min (LC method D).

Example 98: preparation of (14S) -12, 12-bis (trideutero) methyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl [ ] -methyl]Propoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 292)

Step 1: (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-bis (trideuteromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester

To 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]To a solution of pyridine-3-carboxylic acid (175mg, 0.4490mmol) in tetrahydrofuran (1.5mL) was added carbonyldiimidazole (86mg, 0.5070 mmol) and the mixture was stirred at ambient temperature for 90min to this solution was added a solution containing (4S) -4- [3- [ (6-sulfamoyl-2-pyridyl) amino]Propyl radical]-tert-butyl 2, 2-bis (Trideuteromethyl) pyrrolidine-1-carboxylate (140mg, 0.3345 mmol) in tetrahydrofuran (1mL) followed by addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (135 μ L, 0.9027mmol) and the mixture stirred at ambient temperature for 16 h.the reaction was diluted with water (5mL) and the mixture was slowly acidified with hydrochloric acid (1.7mL, 1M, 1.700 mmol.) the mixture was extracted with ethyl acetate (10mL) and the organic phase was separated and concentrated in vacuo to give the crude product which was subjected to 30 g reverse phase column chromatography eluting with 50% -100% acetonitrile/water to give (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] amino acid methyl ester ]Propoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-tert-butyl 2, 2-bis (trideuteromethyl) pyrrolidine-1-carboxylate (200mg, 76%). ESI-MS M/z calculated 789.31696, experimental 790.4 (M +1)⁺(ii) a Retention time: 3.47min (LC method D).

Step 2: n- [ [6- [3- [ (3S) -5, 5-bis (Trideuteromethyl) pyrrolidin-3-yl ] propylamino ] -2-pyridyl ] sulfonyl ] -2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carboxamide (trifluoroacetate)

To a solution containing (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Propoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]To tert-butyl (200mg, 0.2531mmol) of-2, 2-bis (Trideuteromethyl) pyrrolidine-1-carboxylate in dichloromethane (3mL) and toluene (1mL) was added trifluoroacetic acid (200. mu.L, 2.596 mmol). The mixture was stirred at ambient temperature for 18 h. The solvent was removed in vacuo and the residue was treated with 10mL of toluene and concentrated in vacuo to give N- [ [6- [3- [ (3S) -5, 5-bis (Trideuteromethyl) pyrrolidin-3-yl]Propylamino group]-2-pyridyl]Sulfonyl radical]-2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxamide (trifluoroacetate) (204mg, 100%). ESI-MS M/z calculated 689.2645, Experimental 690.3(M +1) ⁺(ii) a Retention time: 2.23min (LC method D).

And step 3: (14S) -12, 12-bis (Trideuterium) methyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 292)

To N- [ [6- [3- [ (3S) -5, 5-bis (Trideuteromethyl) pyrrolidin-3-yl group]Propylamino group]-2-pyridyl]Sulfonyl radical]-2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]To a solution of pyridine-3-carboxamide (trifluoroacetate) (200mg, 0.2487mmol) in NMP (6mL) was added potassium carbonate (180mg, 1.302 mmol). The mixture was purged with nitrogen for 5min and then heated at 135 ℃ for 22 h. The reaction mixture was cooled to ambient temperature and diluted with water (10 mL). The mixture was acidified carefully with hydrochloric acid (500 μ L, 6M, 3.000mmol), the slurry was extracted with ethyl acetate (15mL) and the organic phase was washed with brine. Concentrating the organic phase under vacuum 30g of reverse phase column chromatography on the crude product, eluting with a gradient of 50% to 100% acetonitrile/water to give a foam, drying the foam in a vacuum oven at 45 ℃ for 48h to give (14S) -12, 12 -bis (trideuterio) methyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 292) (45.2mg, 27%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.51(s, 1H), 8.21(d, J ═ 2.7Hz, 1H), 7.81(d, J ═ 8.3Hz, 1H), 7.63-7.51(m, 1H), 7.05(d, J ═ 7.2Hz, 1H), 6.99(s, 1H), 6.91(d, J ═ 8.2Hz, 1H), 6.71(d, J ═ 8.4Hz, 1H), 6.12(d, J ═ 2.7Hz, 1H), 4.20(t, J ═ 6.2Hz, 2H), 3.92(s, 1H), 3.15(s, 1H), 2.95(d, J ═ 13.4Hz, 1H), 2.75-2.65(m, 1H), 2.10(d, J ═ 18, 1H), 1H, 3.5 (m, 3.5, 3.7H), 3.7H, 1H, 3.7H, 1H, 3.7H, 1H, 3.7H, 5(m ═ 3, 3.7H), 3.7H), experimental value 654.4(M +1)⁺(ii) a Retention time: 2.21min (LC method B).

Example 99: preparation of (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } -2-hydroxyethoxy) -1H-pyrazol-1-yl radical]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 294) and (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } -2-hydroxyethoxy) -1H-pyrazol-1-yl radical]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 293)

Step 1: (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } -2-hydroxyethoxy) -1H-pyrazol-1-yl radical]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaene-2, 2, 4-trione (diastereomer 1)(Compound 294) and (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } -2-hydroxyethoxy) -1H-pyrazol-1-yl radical]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 293)

(14S) -8- [3- (2- { dispiro [2.0.2.1 ] was chromatographed by SFC using ChiralCel AS-H (250X 10mm column, 5 μm particle size) and 38% acetonitrile/methanol (90: 10)/60% carbon dioxide mobile phase (10mL/min over 28.0min) ]Hept-7-yl } -2-hydroxyethoxy) -1H-pyrazol-1-yl radical]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (62mg, 0.09030mmol) was subjected to chiral separation (injection volume 70 μ L, 23mg/mL solution in acetonitrile/methanol (90: 10)) to give (14S) -8- [3- (2- { dispiro [2.0.2.1 ] as a white solid of the first diastereomer to be eluted]Hept-7-yl } -2-hydroxyethoxy) -1H-pyrazol-1-yl radical]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 294) (16.4mg, 55%);¹h NMR (400MHz, dimethylsulfoxide-d)₆)12.51(s，1H)，8.20(d，J＝2.7Hz，1H)， 7.82(d，J＝8.2Hz，1H)，7.58(t，J＝7.8Hz，1H)，7.05(d，J＝7.2Hz，1H)，6.99(d，J＝ 9.1Hz，1H)，6.91(d，J＝8.2Hz，1H)，6.71(d，J＝8.5Hz，1H)，6.09(d，J＝2.7Hz， 1H)，4.87(dd，J＝5.2，1.3Hz，1H)，4.09(d，J＝5.5Hz，2H)，3.92(d，J＝12.6Hz，1H)， 3.57(dt，J＝9.2，5.3Hz，1H)，3.16(d，J＝10.0Hz，1H)，2.95(d，J＝13.3Hz，1H)， 2.69(d，J＝9.6Hz，1H)，2.12(s，1H)，1.86(dd，J＝11.9，5.2Hz，1H)，1.76(s，1H)， 1.60(s，3H)，1.59-1.53(m，3H)，1.52(s，3H)，1.31(q，J＝9.4，7.1Hz，1H) 1.08(ddd, J ═ 8.9, 5.3, 3.6Hz, 1H), 0.95-0.88(m, 1H), 0.84(ddd, J ═ 8.8, 5.2, 3.7Hz, 1H), 0.73(ddd, J ═ 8.0, 4.8, 3.3Hz, 1H), 0.63(ddd, J ═ 8.7, 5.2, 3.6Hz, 2H), 0.60-0.54 (m, 2H), 0.52(dt, J ═ 8.4, 3.8Hz, 1H); ESI-MS M/z calculated 633.2733, Experimental 634.2 (M +1)⁺(ii) a Retention time: 1.95min (LC method B) and (14S) -8- [3- (2- { dispiro [2.0.2.1 ] as a white solid for the second diastereomer to be eluted ]Hept-7-yl } -2-hydroxyethoxy) -1H-pyrazol-1-yl radical]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 293) (17.3mg, 60%);¹h NMR (400MHz, dimethylsulfoxide-d)₆)12.52(s, 1H), 8.20(d, J ═ 2.8Hz, 1H), 7.82(d, J ═ 8.2Hz, 1H), 7.58(t, J ═ 7.9Hz, 1H), 7.05(d, J ═ 7.2Hz, 1H), 6.99(d, J ═ 8.9Hz, 1H), 6.91(d, J ═ 8.2Hz, 1H), 6.71(d, J ═ 8.5Hz, 1H), 6.09(d, J ═ 2.7Hz, 1H), 4.88(d, J ═ 5.2Hz, 1H), 4.15-4.05(m, 2H), 3.92(d, J ═ 11.8, 1H), 3.57 (d, J ═ 9.2, 8, 1H), 3.57 (d, J ═ 5.2, 1H), 4.15-4.05(m, 2H), 3.92(d, J ═ 11.8, 1H), 1H), 3.57 (d, 3.53, 1H), 1H), 1.5 (d, 1H), 6.5, 1H), 1H, 6.5, 1H), 1H, 6, j ═ 2.2Hz, 3H), 1.31(d, J ═ 12.4Hz, 1H), 1.08(ddd, J ═ 8.9, 5.3, 3.6Hz, 1H), 0.92(dd, J ═ 8.6, 4.2Hz, 1H), 0.84(ddt, J ═ 7.4, 5.2, 3.5Hz, 2H), 0.74-0.70(m, 1H), 0.63(ddd, J ═ 8.9, 5.3, 3.8Hz, 1H), 0.59-0.54(m, 2H), 0.54-0.48 (m, 1H); ESI-MS M/z calculated 633.2733, Experimental 634.2(M +1) ⁺(ii) a Retention time: 1.95 min (LC method B).

Example 100: preparation of (14S) -8- (3- { 3-hydroxy-3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) -12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 295)

Step 1: 3-oxo-3- [1- (trifluoromethyl) cyclopropyl ] propanoic acid ethyl ester

To a suspension of (3-ethoxy-3-oxo-propionyl) potassium oxo (23.197g, 136.29mmol) in acetonitrile (200mL) was added triethylamine (21.014g, 28.945mL, 207.67mmol) and dichloromagnesium (15.448g, 162.25mmol), the mixture was stirred at room temperature for 2h, a mixture of carbonyldiimidazole (12.628g, 77.878mmol) and 1- (trifluoromethyl) cyclopropanecarboxylic acid (10g, 64.898mmol) in acetonitrile (40mL) was added to the mixture, and the combined mixture was stirred overnight, the mixture was diluted with ethyl acetate (250mL) and washed with water (500mL) and brine (500mL) before drying over sodium sulfate, followed by filtration. After concentrating the filtrate in vacuo, the organic residue was purified by silica gel chromatography, eluting with 30% hexane-ethyl acetate, to give 3-oxo-3- [1- (trifluoromethyl) cyclopropyl ] methyl ester ]Ethyl propionate (3.875g, 25%).¹H NMR(250MHz， CDCl₃)4.17(qd，J＝7.1，0.6Hz，2H)，3.73(s，2H)，1.41-1.32(m，3H)，1.24(td，J＝ 7.1，0.6Hz，4H).

Step 2: 3-hydroxy-3- [1- (trifluoromethyl) cyclopropyl ] propanoic acid ethyl ester

To 3-oxo-3- [1- (trifluoromethyl) cyclopropyl at-78 deg.C]To a solution of ethyl propionate (3.513g, 15.671mmol) in EtOH (35.130mL) was added NaBH₄(652.16mg, 0.6901mL, 17.238 mmol.) Prior to quenching with 1M aqueous hydrochloric acid (35mL), the mixture was stirred at 0 deg.C. the organic layer was extracted with ethyl acetate (3X 100mL) before being washed with brine (100mL) and dried over sodium sulfate, the mixture was filtered and the filtrate was concentrated in vacuo to give 3-hydroxy-3- [1- (trifluoromethyl) cyclopropyl]Ethyl propionate (3.31g, 63%).¹H NMR (250MHz，CDCl₃)4.09(d，J＝7.1Hz，2H)，3.89(s，1H)，2.70(d，J＝3.1Hz，2H)， 1.26-1.21(m，3H)，0.96(d，J＝6.9Hz，4H)。

And step 3: 3- [ tert-butyl (dimethyl) silyl ] oxy-3- [1- (trifluoromethyl) cyclopropyl ] propanoic acid ethyl ester

To 3-hydroxy-3- [1- (trifluoromethyl)) cyclopropyl at 0 deg.C]To a solution of ethyl propionate (3.19g, 14.103mmol) in dichloromethane (63.800mL) were added 2, 6-lutidine (3.1734g, 3.4300mL, 29.616 mmol) and [ tert-butyl (dimethyl) silyl group]Trifluoromethanesulfonate (5.5918g, 4.8624mL, 21.154 mmol). The reaction was stirred at room temperature for 3h, the solution was diluted with diethyl ether (60mL) and washed with 1M hydrochloric acid (60mL), saturated sodium bicarbonate (60mL) and brine (60mL), the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 3- [ tert-butyl (dimethyl) silyl ] silane as a clear liquid ]Oxy-3- [1- (trifluoromethyl) cyclopropyl]Ethyl propionate (3.51g, 72%).¹H NMR(250MHz，CDCl₃)4.12(q，J＝7.2Hz，2H)， 3.95(ddd，J＝8.5，3.9，1.1Hz，1H)，2.71-2.59(m，2H)，1.33-1.19(m，3H)，0.89- 0.87(m，3H)，0.88-0.82(m，6H)，0.11-0.05(m，4H)，0.04-0.01(m，6H).

And 4, step 4: 1- [1- (trifluoromethyl) cyclopropyl ] propane-1, 3-diol

To 3- [ tert-butyl (dimethyl) silyl group at 0 DEG C]Oxy-3- [1- (trifluoromethyl) cyclopropyl]To a solution of ethyl propionate (3.51g, 10.310mmol) in anhydrous tetrahydrofuran (50mL) was added lithium aluminum hydride (469.57 mg, 0.5121mL, 12.372mmol). The reaction was stirred at 0 ℃ for 1 h. The reaction was diluted with diethyl ether (50mL) and then quenched with water (0.5mL), 15% sodium hydroxide (0.5mL) and water (1.5mL) at 0 deg.C and allowed to dryThe filtrate was concentrated in vacuo and purified by silica gel chromatography using a gradient of 100% hexane to 100% ethyl acetate to give 1- [1- (trifluoromethyl) cyclopropyl as a clear liquid]Propane-1, 3-diol (1.493g, 73%).¹H NMR (250MHz, chloroform-d) 4.03-3.67(m, 3H), 2.83(d, J ═ 4.2Hz, 1H), 2.16(s, 1H), 1.96-1.74(m, 2H), 1.13-0.93(m, 2H), 0.93-0.69(m, 2H).

And 5: 3- [ 3-hydroxy-3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazole-1-carboxylic acid tert-butyl ester

To 1- [1- (trifluoromethyl) cyclopropyl at 0 deg.C]Propane-1, 3-diol (1.493g, 7.5397mmol), 3-hydroxypyrazole-1-carboxylic acid tert-butyl ester (1.4582g, 7.9167mmol) and triphenylphosphine (3.9550g, 15.079mmol) in anhydrous tetrahydrofuran (30mL) DIAD (3.0491g, 15.079mmol) was added dropwise, the reaction mixture was stirred at room temperature for 3h, the reaction was quenched with water (30mL) and tetrahydrofuran was removed under reduced pressure the residue was extracted with ethyl acetate (3X 30mL), the combined organic layers were washed with brine (30mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, the residue was purified by silica gel chromatography using a gradient of 0% to 50% ethyl acetate/hexane to give 3- [ 3-hydroxy-3- [1- (trifluoromethyl) cyclopropyl as a clear liquid ]Propoxy group]Pyrazole-1-carboxylic acid tert-butyl ester (1.04g, 37%).¹H NMR (250MHz, chloroform-d) 7.84(d, J ═ 2.9Hz, 1H), 5.85(d, J ═ 2.9Hz, 1H), 4.58(ddd, J ═ 10.9, 9.4, 3.8Hz, 1H), 4.37(dt, J ═ 10.6, 4.6 Hz, 1H), 3.79(d, J ═ 10.6Hz, 1H), 3.70(s, 1H), 2.31-2.07(M, 1H), 1.97-1.75(M, 1H), 1.60(s, 9H), 1.06-0.68(M, 4H), ESI-MS M/z calculated value 350.1453, experimental value 351.1 (M +1)⁺(ii) a Retention time: 4.97min (LC method Q).

Step 6: tert-butyl-dimethyl- [3- (1H-pyrazol-3-yloxy) -1- [1- (trifluoromethyl) cyclopropyl ] propoxy ] silane

To 3- [ 3-hydroxy-3- [1- (trifluoromethyl) cyclopropyl at room temperature]Propoxy group]Pyrazole-1-carboxylic acid tert-butyl ester (1.04g, 2.9686mmol) and 2, 6-lutidine (1.5905g, 1.7191mL, 14.843mmol) in anhydrous dichloromethane (50mL) were added dropwise [ tert-butyl (dimethyl) silyl group]Trifluoromethanesulfonate (3.1387g, 2.7269mL, 11.874 mmol.) the reaction mixture was stirred at room temperature for 2 days, then quenched with 1N hydrochloric acid (50 mL). The two layers were separated, the aqueous layer was extracted with dichloromethane (2 × 50mL), the combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate (50mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of 0% to 30% acetone/hexane to give tert-butyl-dimethyl- [3- (1H-pyrazol-3-yloxy) -1- [1- (trifluoromethyl) cyclopropyl ] as a pale yellow oil ]Propoxy group]Silane (895.1mg, 82%).¹H NMR (250MHz, dimethylsulfoxide-d)₆)11.84(s, 1H), 7.49(s, 1H), 5.62(s, 1H), 4.16-3.98(m, 2H), 3.64-3.55(m, 1H), 2.12-1.85(m, 2H), 1.07-0.94 (m, 2H), 0.85(s, 9H), 0.79-0.62(m, 2H), 0.06(s, 3H), -0.02(s, 3H). ESI-MS M/z calculated 364.1794, Experimental 365.1(M +1)⁺(ii) a Retention time: 6.52min (LC method Q).

And 7: 6- [3- [3- [ tert-butyl (dimethyl) silyl ] oxy-3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] -2-chloro-pyridine-3-carboxylic acid tert-butyl ester

To a mixture of tert-butyl 2, 6-dichloropyridine-3-carboxylate (378mg, 1.524mmol) and tert-butyl-dimethyl- [3- (1H-pyrazol-3-yloxy) -1- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Propoxy group]To a solution of silane (500mg, 1.372mmol) in dimethyl sulfoxide (10mL) was added potassium carbonate (234mg, 1.693mmol), followed by the addition of 1, 4-diazabicyclo [2.2.2 ]]Octane (37mg, 0.3298 mmol.) the heterogeneous mixture was stirred at room temperature under nitrogen for 16h, the reaction mixture was quenched with ice andstir 15min the resulting white solid was collected by filtration and washed with water. The solid was dissolved in dichloromethane and dried over magnesium sulfate. The mixture was filtered and the filtrate evaporated and the resulting brown residue purified by silica gel column chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate to give 6- [3- [ tert-butyl (dimethyl) silyl ] as a white solid ]Oxy-3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]-2-chloro-pyridine-3-carboxylic acid tert-butyl ester (640mg, 81%). ESI-MS M/z calculated 575.2194, Experimental 576.36(M +1)⁺(ii) a Retention time: 0.85min (LC method L).

And 8: 6- [3- [3- [ tert-butyl (dimethyl) silyl ] oxy-3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] -2-chloro-pyridine-3-carboxylic acid

Reacting 6- [3- [3- [ tert-butyl (dimethyl) silyl]Oxy-3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]Tert-butyl-2-chloro-pyridine-3-carboxylate (640mg, 1.111mmol) was dissolved in a premixed mixture of dichloromethane (2mL) and trifluoroacetic acid (500 μ L, 6.490mmol) and the reaction was stirred at room temperature for 60 min. The reaction was evaporated and the resulting oil was partitioned between ethyl acetate and a saturated solution of sodium bicarbonate the aqueous portion was extracted two more times with ethyl acetate, then the organics were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give 6- [3- [3- [ tert-butyl (dimethyl) silyl]Oxy-3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]2-chloro-pyridine-3-carboxylic acid (540mg, 93%). ESI-MS M/z calculated 519.1568, experimental 520.3(M +1)⁺(ii) a Retention time: 0.6min (LC method L).

And step 9: (4S) -4- [3- [ [6- [ [6- [3- [3- [ tert-butyl (dimethyl) silyl ] oxy-3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] -2-chloro-pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

Reacting 6- [3- [3- [ tert-butyl (dimethyl) silyl]Oxy-3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]-2-chloro-pyridine-3-carboxylic acid (540mg, 1.038mmol) and carbonyldiimidazole (204mg, 1.258mmol) (newly recrystallized from tetrahydrofuran, washed with low temperature ether, and dried under vacuum) were combined in tetrahydrofuran (5mL) and stirred at room temperature for 2h, then (4S) -2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (431mg, 1.045mmol) followed by the addition of 1, 8-diazabicyclo [ 5.4.0%]Undec-7-ene (800. mu.L, 5.350mmol) and the reaction stirred at room temperature for 14 h. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to a light brown oil which was purified by silica gel chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate to give (4S) -4- [3- [ [6- [ [6- [3- [ tert-butyl (dimethyl) silanyl ] 6- [3- [3- [ tert-butyl (dimethyl) silanyl ] as a white solid ]Oxy-3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]-2-chloro-pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (572mg, 60%). ESI-MS M/z calculated 913.36066, experimental 914.5 (M +1)⁺(ii) a Retention time: 0.79min (LC method L).

Step 10: (14S) -8- (3- { 3-hydroxy-3- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Propoxy } -1H-pyrazol-1-yl) -12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 295)

Reacting (4S) -4- [3- [ [6- [ [6- [3- [3- [ tert-butyl (dimethyl) silyl) group at room temperature]Oxy-3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]-2-chloro-pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2A solution of tert-butyl 2-dimethyl-pyrrolidine-1-carboxylate (572mg, 0.6254mmol) in dichloromethane (4.8mL) and trifluoroacetic acid (1.2mL, 15.68mmol) was stirred for 4 h. The solvent was evaporated and the residue was dissolved in ethyl acetate, washed with 2mL of a saturated solution of sodium bicarbonate, and the solvent was removed and dried in vacuo

Molecular sieves and stirring the reaction mixture for 10min then cesium fluoride (301mg, 1.982mmol) and potassium carbonate (284mg, 2.055mmol) were added and the reaction mixture was heated at 150 ℃ for 16h the reaction mixture was cooled to room temperature and filtered through celite and a saturated solution of ammonium chloride was added to the filtrate the mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting brown residue was purified by silica gel column chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate to give (14S) -8- (3- { 3-hydroxy-3- [1- (trifluoromethyl) cyclopropyl ] as an off-white solid]Propoxy } -1H-pyrazol-1-yl) -12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 295) (192mg, 46%).¹H NMR (400MHz, chloroform-d) 9.77(s, 1H), 8.20(dd, J ═ 2.7, 1.1Hz, 1H), 8.02(dd, J ═ 8.4, 0.9Hz, 1H), 7.54(d, J ═ 7.5Hz, 1H), 7.47(dt, J ═ 7.4, 1.1Hz, 1H), 7.15(d, J ═ 8.3Hz, 1H), 6.54(d, J ═ 8.2Hz, 1H), 5.92 (d, J ═ 2.7Hz, 1H), 4.70(s, 1 ddh), 4.57(d, J ═ 11.1, 9.1, 4.0, 2.1Hz, 1H), 4.40(d, J ═ 10.5, 5.1, 3.90(s, 3.3H), 3.7H, 3.3.3, 3.3H, 3.7H, 3H, 3.3, 3H, 3.3H, 3J ═ 8, 1H, 3, 2H) 1.70-1.49(m, 10H), 1.09-0.93(m, 2H), 0.92-0.80(m, 2H). ESI-MS M/z calculated 663.24506, Experimental 664.17(M +1) ⁺(ii) a Retention time: 1.93min (LC method B).

Example 101: preparation of (14)S) -8- (3- { 3-hydroxy-3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) -12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 296) and (14S) -8- (3- { 3-hydroxy-3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) -12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 297)

Step 1: (14S) -8- (3- { 3-hydroxy-3- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Propoxy } -1H-pyrazol-1-yl) -12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 296) and (14S) -8- (3- { 3-hydroxy-3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) -12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 297)

(14S) -8- (3- { 3-hydroxy-3- [1- (trifluoromethyl) cyclopropyl) amino acid sequence by SFC chromatography using a Chiral Pak IG (250X 21.2mm) column (5 μm particle size) and a mobile phase of 38% methanol, 62% carbon dioxide (70mL/min, over 8.0min)]Propoxy } -1H-pyrazol-1-yl) -12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (187 mg) was subjected to chiral separation (injection volume 500. mu.L, about 31 mg/m)L in acetonitrile: methanol (90: 10)) to give (14S) -8- (3- { 3-hydroxy-3- [1- (trifluoromethyl) cyclopropyl ] as a white solid as the first diastereomer to elute]Propoxy } -1H-pyrazol-1-yl) -12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 296) (59.2mg, 32%);¹h NMR (400MHz, dimethylsulfoxide-d)₆)12.50(s, 1H), 8.21(d, J ═ 2.8Hz, 1H), 7.82(d, J ═ 8.2Hz, 1H), 7.58(dd, J ═ 8.5, 7.2Hz, 1H), 7.05(d, J ═ 7.1Hz, 1H), 6.98(d, J ═ 8.5Hz, 1H), 6.92(d, J ═ 8.2Hz, 1H), 6.71(d, J ═ 8.5Hz, 1H), 6.13(d, J ═ 2.7Hz, 1H), 5.23(d, J ═ 5.7Hz, 1H), 4.31(dd, J ═ 8.2, 5.6 Hz, 2H), 3.92(d, J ═ 12.8, 1H), 3.69(t, t ═ 3.6H), 3.6.6H, 3.6H, 3.92(d, J ═ 12.8, 1H), 3.6 (t, 1H), 3.6, 6.6, 1H, 6 (d, 1H), 6, 6.6H, 1H, 6, 1H, 6, 1H, 6H, 1H, 6, 1H, 6, 1, 2H) 1.52(s, 3H), 1.30 (dt, J ═ 24.6, 12.0Hz, 1H), 0.93-0.81(m, 4H); ESI-MS M/z calculated 663.24506, Experimental 664.11(M +1) ⁺(ii) a Retention time: 1.94min (LC method B) and (14S) -8- (3- { 3-hydroxy-3- [1- (trifluoromethyl) cyclopropyl ] as a white solid as the second diastereomer to be eluted]Propoxy } -1H-pyrazol-1-yl) -12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 297) (57.8mg, 31%);¹h NMR (400MHz, dimethylsulfoxide-d)₆)12.51(s，1H)，8.21(d，J＝2.7 Hz，1H)，7.81(d，J＝8.2Hz，1H)，7.63-7.54(m，1H)，7.05(d，J＝7.1Hz，1H)，6.98 (s，1H)，6.92(d，J＝8.2Hz，1H)，6.71(d，J＝8.5Hz，1H)，6.12(d，J＝2.7Hz，1H)， 5.24(d，J＝5.7Hz，1H)，4.31(dd，J＝7.6，5.0Hz，2H)，3.92(d，J＝13.3Hz，1H)，3.69 (t，J＝7.4Hz，1H)，3.17(d，J＝5.0Hz，1H)，2.95(d，J＝13.4Hz，1H)，2.69(d，J＝ 16.0Hz，1H)，2.20-2.01(m，2H)，1.83(ddd, J ═ 25.2, 11.4, 6.3Hz, 3H), 1.61(s, 3H), 1.57(d, J ═ 12.7Hz, 2H), 1.52(s, 3H), 1.31(q, J ═ 12.5, 12.1Hz, 1H), 0.87(d, J ═ 8.1 Hz, 4H); ESI-MS M/z calculated 663.24506, Experimental 664.11(M +1)⁺(ii) a Retention time: 1.94min (LC method B).

Example 102: preparation of (14S) -8- [3- (2- { dispiro [2.0.2.1]]Hept-7-yl } -1, 1, 2, 2-tetradeuterium-ethoxy) -1H-pyrazol-1-yl radical]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5(10), 6, 8, 19(23), 20-hexaen-2, 2, 4-trione (compound 299)

Step 1: 1, 1, 2, 2-tetradeuterium-2-dispiro [2.0.2.1] hept-7-yl-ethanol

Lithium aluminum deuteride (2.8120g, 68.955 mmol) was weighed under a nitrogen balloon in a reaction flask placed in an ice-water bath, tetrahydrofuran (160mL) was slowly added, the mixture was stirred in an ice-water bath for 10min, 2-dideutero-2-dispiro [2.0.2.1] dissolved alone in tetrahydrofuran (40mL) was added in a rapid dropwise fashion by syringe]Hept-7-yl-acetic acid (10.85g, 63.326 mmol.) the mixture was allowed to warm to room temperature and stirred at room temperature for 15 h. This was then re-cooled in an ice-water bath, rochelle salt solution was added in small portions to quench the unreacted lithium aluminum deuteride, after quenching was complete, rochelle solution (200mL) was added again, the mixture was stirred at room temperature for 10min and the layers were separated. The aqueous layer was extracted with ether (3X 60mL) the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated at 30 ℃ and 100mbar to give 1, 1, 2, 2-tetradeuterium-2-dispiro [2.0.2.1] as a yellowish liquid]Hept-7-yl-ethanol (9.72g, 97%, 90% purity).¹H NMR (250MHz, dimethylsulfoxide-d)₆)1.34(s，1H)，0.76(q，J＝8.6，7.1Hz，4H)，0.67-0.53(m，2H)，0.53- 0.33(m，2H)。

Step 2: 3- (1, 1, 2, 2-Tetradeuterium-2-dispiro [2.0.2.1] hept-7-yl-ethoxy) pyrazole-1-carboxylic acid tert-butyl ester

To 5-oxo-1H-pyrazole-2-carboxylic acid tert-butyl ester (6.235g, 33.85mmol) and 1, 1, 2, 2-tetradeuterium-2-dispiro [2.0.2.1] ]To a solution of hept-7-yl-ethanol (5.0g, 35.15mmol) in tetrahydrofuran (80mL) was added triphenylphosphine (9.37g, 35.72 mmol). Diisopropyl azodicarboxylate (7.0mL, 35.55mmol) was added slowly dropwise to the mixture over 10min (an exotherm was noted). The reaction mixture was stirred at room temperature for 2 h. The tetrahydrofuran was removed in vacuo. The crude product was purified by silica gel chromatography using a gentle gradient of 100% hexane to 20% ethyl acetate/hexane to give 3- (1, 1, 2, 2-tetradeuterium-2-dispiro [2.0.2.1] as a clear slurry]Hept-7-yl-ethoxy) pyrazole-1-carboxylic acid tert-butyl ester (7.4g, 71%).¹H NMR (400MHz, chloroform-d) 7.82(d, J ═ 2.9Hz, 1H), 5.84(d, J ═ 2.9Hz, 1H), 1.61(s, 9H), 1.44(s, 1H), 0.83(q, J ═ 1.9Hz, 4H), 0.68-0.61 (M, 2H), 0.52-0.45(M, 2H), ESI-MS M/z calculated 308.2038, experimental 309.2 (M +1)⁺(ii) a Retention time: 2.08min (LC method E).

And step 3: 3- (1, 1, 2, 2-tetradeuterium-2-dispiro [2.0.2.1] hept-7-yl-ethoxy) -1H-pyrazole

To a mixture containing 3- (1, 1, 2, 2-tetradeuterium-2-dispiro [2.0.2.1]]Hept-7-yl-ethoxy) pyrazole-1-carboxylic acid tert-butyl ester (7.4g, 23.99mmol) in a flask was added dichloromethane (125mL) and trifluoroacetic acid (45mL, 584.1mmol) after 30min, the mixture was evaporated to dryness and neutralized with saturated sodium bicarbonate the reaction was extracted with ethyl acetate and the organic layer was dried over sodium sulfate, filtered and evaporated to afford 3- (1, 1, 2, 2-tetradeuterium-2-dispiro [2.0.2.1] as a colorless oil ]Hept-7-yl-ethoxy) -1H-pyrazole (4.95g, 99%). ESI-MS M/z calculated 208.15137, Experimental 209.2(M +1)⁺(ii) a Retention time: 1.46min (LC method E).

And 4, step 4: 2-chloro-6- [3- (1, 1, 2, 2-tetradeuterium-2-dispiro [2.0.2.1] hept-7-yl-ethoxy) pyrazol-1-yl ] pyridine-3-carboxylic acid tert-butyl ester

2, 6-dichloropyridine-3-carboxylic acid tert-butyl ester (6.05g, 24.38mmol), 3- (1, 1, 2, 2-tetradeuterium-2-dispiro [2.0.2.1]]Hept-7-yl-ethoxy) -1H-pyrazole (5.04g, 24.20mmol) and potassium carbonate (7.4g, 53.54 mmol) were combined in anhydrous dimethylsulfoxide (125 mL). Addition of 1, 4-diazabicyclo [2.2.2]Octane (545mg, 4.859mmol) and the mixture stirred at room temperature under nitrogen for 18 h. The reaction mixture was diluted with water (75mL) and stirred for 15 min. The resulting solid formed was filtered, collected and dried under vacuum overnight. The remaining filtrate was diluted with ethyl acetate and washed with water (3X 50 mL). The organic layers were combined and washed with brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 100% hexane to 60% ethyl acetate/hexane to give a light yellow oil which was dried in vacuo to give a light yellow solid which was combined with the previously filtered solid to give 2-chloro-6- [3- (1, 1, 2, 2-tetradeuterium-2-dispiro [2.0.2.1] ]Hept-7-yl-ethoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (9.95g, 98%).¹H NMR (400MHz, chloroform-d) 8.35(d, J ═ 2.9Hz, 1H), 8.19(d, J ═ 8.5Hz, 1H), 7.69 (d, J ═ 8.4Hz, 1H), 5.94(d, J ═ 2.8Hz, 1H), 1.62(s, 9H), 1.48(s, 1H), 0.88-0.81(M, 4H), 0.70-0.62(M, 2H), 0.51(dt, J ═ 10.7, 1.5Hz, 2H), ESI-MS M/z calculated 419.19138, experimental value 420.2(M +1)⁺(ii) a Retention time: 2.58min (LC method E).

And 5: 2-chloro-6- [3- (1, 1, 2, 2-tetradeuterium-2-dispiro [2.0.2.1] hept-7-yl-ethoxy) pyrazol-1-yl ] pyridine-3-carboxylic acid

2-chloro-6- [3- (1, 1, 2, 2-tetradeuterium-2-dispiro [2.0.2.1]]Hept-7-yl-ethoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (13.15g, 31.31mmol) was dissolved in dichloromethane (250 mL). To the mixture was slowly added trifluoroacetic acid (50mL, 649.0mmol) and the mixture was kept stirring at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure to a solid which was then slurried in diethyl ether and filtered (2 ×) to yield a solid which was recrystallized from dichloromethane and collected by filtration to yield a white solid (crop 1.) the product was still in the dichloromethane filtrate, the dichloromethane filtrate was evaporated to yield an off-white solid which was dissolved in ethyl acetate and washed with 5N sodium hydroxide (2 ×), then 1N hydrochloric acid (1 ×), followed by drying (sodium sulfate), filtration and concentration to a white solid which was subjected to 150g of reverse phase C ₁₈Column chromatography, dimethyl sulfoxide loading and elution with a gradient of 50% to 100% acetonitrile/water to yield (after combining with filtered crop 1 solid) 2-chloro-6- [3- (1, 1, 2, 2-tetradeuterium-2-dispiro [2.0.2.1 ]) as a white solid]Hept-7-yl-ethoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (9.05g, 79%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)13.61(s, 1H), 8.53-8.28(m, 2H), 7.72(d, J ═ 8.4Hz, 1H), 6.17(d, J ═ 2.9Hz, 1H), 1.46(s, 1H), 0.87-0.79(m, 4H), 0.68-0.61(m, 2H), 0.53-0.45(m, 2H). ESI-MS M/z calculated 363.12878, Experimental 364.3(M +1)⁺(ii) a Retention time: 1.45min (LC method G).

Step 6: (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (1, 1, 2, 2-tetradeuterium-2-dispiro [2.0.2.1] hept-7-yl-ethoxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To 2-chloro-6- [3- (1, 1, 2, 2-tetradeuterium-2-dispiro [2.0 ].2.1]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (200mg, 0.5497mmol) in tetrahydrofuran (1.5mL) carbonyl diimidazole (110 mg, 0.6784mmol) was added (recrystallized from tetrahydrofuran) and the mixture was stirred at room temperature for 3h, followed by addition of (4S) -2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino as a solution in tetrahydrofuran (500. mu.L) ]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (240mg, 0.5818mmol) and subsequent addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (250 μ L, 1.672mmol) and the resulting mixture stirred at room temperature for 18 h. The reaction was diluted with water and ethyl acetate, followed by the addition of hydrochloric acid (600 μ L, 6M, 3.600mmol) (then aqueous layer pH 1), the layers were separated, and the organic layer was washed with water (1 ×) and brine (1 ×), then dried over sodium sulfate, filtered and concentrated to a white foam which was subjected to C₁₈Purifying with reverse phase column, eluting with 50% -100% acetonitrile/water gradient to obtain (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (1, 1, 2, 2-tetradeuterium-2-dispiro [2.0.2.1 ]) as off-white solid]Hept-7-yl-ethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (190mg, 46%). ESI-MS M/z calculated 757.33264, Experimental 758.3(M +1)⁺(ii) a Retention time: 2.14min (LC method G).

And 7: (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } -1, 1, 2, 2-tetradeuterium-ethoxy) -1H-pyrazol-1-yl radical]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5(10), 6, 8, 19(23), 20-hexaen-2, 2, 4-trione (compound 299)

Mixing (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (1, 1, 2, 2-tetradeuterium-2-dispiro [2.0.2.1 ]]Hept-7-yl-ethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]Tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (160mg, 0.2110mmol) was dissolved in dichloromethane (5mL) and trifluoroacetic acid (525 μ L,6.814mmol) and stirring the resulting mixture at room temperature for 30min the mixture was concentrated to dryness under reduced pressure, 25mL of toluene was added and removed by rotary evaporation 25mL of toluene was added again and removed by rotary evaporation followed by vacuum drying overnight to give a residue which was admixed with potassium carbonate (205 mg, 1.483mmol),

Molecular sieves and NMP (9.5mL) were combined in a vial, purged with nitrogen, capped, heated to 155 ℃ and stirred for 5h, cooled to room temperature, and the mixture was filtered, diluted with ethyl acetate and washed with water (2 × 20mL), then brine₁₈Reverse phase column purification eluting with a gradient of 50% to 100% acetonitrile/water to give material which is then subjected to silica gel column chromatography using a gentle gradient of 100% dichloromethane to 10% methanol/dichloromethane to give (14S) -8- [3- (2- { dispiro [2.0.2.1 ] as an off-white solid ]Hept-7-yl } -1, 1, 2, 2-tetradeuterium-ethoxy) -1H-pyrazol-1-yl radical]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5(10), 6, 8, 19(23), 20-hexaen-2, 2, 4-trione (compound 299) (79.04mg, 60%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.51(s, 1H), 8.20 (d, J ═ 2.8Hz, 1H), 7.81(d, J ═ 8.2Hz, 1H), 7.57(t, J ═ 7.9Hz, 1H), 7.05(d, J ═ 7.1 Hz, 1H), 6.99(s, 1H), 6.91(d, J ═ 8.2Hz, 1H), 6.71(d, J ═ 8.6Hz, 1H), 6.08(d, J ═ 2.8Hz, 1H), 3.92(d, J ═ 12.7Hz, 1H), 3.15(s, 1H), 2.95(d, J ═ 13.3Hz, 1H), 2.78-2.63 (m, 1H), 2.12(s, 1H), 1.85(dd, 8.8H), 1.5 (d, J ═ 1H), 1H), 1.5 (d, 1H, 13.3.3, 1H), 1H, 5(d, 1H, 5(s, 1H), 1H, 5(s, 1H), 1H, 5(s, 5, 1H), 1H, 5, 1H, 1, 2H) 0.53-0.46(M, 2H). ESI-MS M/z calculated 621.3035, Experimental 622.3(M +1)⁺(ii) a Retention time: 1.87min (LC method G).

Example 103: preparation of (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } -2, 2-dideuterium-ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl (20-deuterium) -2 λ ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 298)

Step 1: (4S) -4- [3- [ [ 3-benzyloxy-6- [ [ 2-chloro-6- [3- (2, 2-dideuterio-2-dispiro [2.0.2.1] hept-7-yl-ethoxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- (2, 2-dideuterio-2-dispiro [2.0.2.1]]Hept-7-yl-ethoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (1.5g, 4.146mmol) and carbonyldiimidazole (831mg, 5.125mmol) (newly recrystallized from tetrahydrofuran, washed with low temperature ether and dried under high vacuum) were combined in tetrahydrofuran (10mL) and stirred at room temperature for 2 h. Subsequently, (4S)4- [3- [ (3-benzyloxy-6-sulfamoyl-2-pyridyl) amino group is added]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.5g, 2.892mmol) followed by addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (3.2 mL, 21.40mmol) and the reaction stirred at room temperature for 14h. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The resulting brown residue was purified by silica gel column chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate to give (4S) -4- [3- [ [ 3-benzyloxy-6- [ [ 2-chloro-6- [3- (2, 2-didehydro-2-dispiro [2.0.2.1 ]) as an off-white solid ]Hept-7-yl-ethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.2g, 62%). ESI-MS M/z calculated 861.36194, Experimental value 862.3(M +1)⁺(ii) a Retention time: 0.76min (LC method L).

Step 2: (14S) -20- (benzyloxy) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } (2, 2-dideuterio) ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione

(4S)4- [3- [ [ 3-benzyloxy-6- [ [ 2-chloro-6- [3- (2, 2-dideuterio-2-dispiro [2.0.2.1 ]]Hept-7-yl-ethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-a solution of tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (2.2g, 2.551mmol) in dichloromethane (16mL) and trifluoroacetic acid (4mL, 52.27 mmol) was stirred for 2h

MS, and stir the mixture for 10 min. Subsequently, cesium fluoride (1.2g, 7.900mmol) and potassium carbonate (1.1g, 7.959mmol) were added and the reaction mixture was heated at 150 ℃ for 16 h. The reaction mixture was cooled to room temperature and filtered through celite, washed with ethyl acetate, and a saturated solution of ammonium chloride was added. The mixture was separated and the aqueous layer was extracted with ethyl acetate the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting brown residue was purified by column chromatography on silica gel using a gentle gradient of 100% hexane to 100% ethyl acetate to give (14S) -20- (benzyloxy) -8- [3- (2- { dispiro [2.0.2.1 ] as an off-white solid]Hept-7-yl } (2, 2-dideuterio) ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (1.26g, 68%).¹H NMR (400MHz, chloroform-d) 9.99(s, 1H), 8.19(d, J ═ 2.7Hz, 1H), 8.05(d, J ═ 8.4Hz, 1H), 7.53(d, J ═ 8.0Hz, 1H), 7.47-7.36(m, 5H), 7.27-7.23(m, 1H), 6.98(d, J ═ 8.1Hz, 1H), 5.89(d, J ═ 2.7Hz, 1H), 5.30(d, J ═ 8.4Hz, 1H), 5.10(s, 2H), 4.23(s, 2H), 3.92(s, 1H), 3.35(dd, J ═ 10.1, 7.4Hz, 1H), 3.19(d, J ═ 14.1Hz, 1H), 3.05(t, J ═ 9.63, 1H), 1H (s, 2H), 1.8.4H, 1H), 1H), 3.19 (t, J ═ 14.1H, 1H), 3.05(t, 9, 1H), 1H, 0.8.8, 5.5.5.5.5H, 5.5 (z, 5, 5.5H, 5(m, 5, 2H), experimental value 726.45(M +1) ⁺(ii) a Retention time: 0.7min (LC method L).

And step 3: (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } (, 2-dideuterio) ethoxy) -1H-pyrazol-1-yl]-20-hydroxy-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione

To (14S) -20- (benzyloxy) -8- [3- (2- { dispiro [2.0.2.1 ] under nitrogen]Hept-7-yl } (2, 2-dideuterio) ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]A stirred solution of tetracos-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (500mg, 0.6888mmol) in EtOH (10mL) was added 10% palladium on carbon (moist, Degussa, 155 mg, 0.1456mmol), the heterogeneous mixture was stirred under a balloon of hydrogen at ambient temperature for 2h, and the black heterogeneous reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give (14S) -8- [3- (2- { dispiro [2.0.2.1 ] as a pale brown solid]Hept-7-yl } (2, 2-dideuterio) ethoxy) -1H-pyrazol-1-yl]-20-hydroxy-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (156mg, 36%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.31(s，1H)，10.84(s，1H)，820(d, J ═ 2.8Hz, 1H), 7.76(d, J ═ 8.2Hz, 1H), 7.07(d, J ═ 7.7Hz, 1H), 6.91(dd, J ═ 9.6, 7.9Hz, 2H), 6.17(s, 1H), 6.07(d, J ═ 2.7 Hz, 1H), 4.20(d, J ═ 1.5Hz, 2H), 3.92(s, 1H), 3.18(s, 1H), 2.99(d, J ═ 13.1Hz, 1H), 2.68(s, 1H), 2.11(d, J ═ 6.6Hz, 1H), 1.97-1.81(M, 2H), 1.66-1.48(M, 9H), 1.45(s, 1H), 1.24(q ═ 6.6Hz, 1H), 0.79(M, 0.84H), 0.83-19 (M, 19H), 2H, 19 (M, 19H), 2H, 19 (M, 3H), 3H), 2H), 1H), 5H, 5⁺(ii) a Retention time: 0.54min (LC method L).

And 4, step 4: (14S) -4-methylbenzene-1-sulfonic acid 8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } (2, 2-dideuterio) ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2, 2, 4-trioxo-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1- (23), 5, 7, 9, 19, 21-hexaen-20-yl esters

To (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } (2, 2-dideuterio) ethoxy) -1H-pyrazol-1-yl]-20-hydroxy-12, 12-dimethyl-2 lambda ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]To a stirred solution of tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (50mg, 0.07864mmol) in dry dichloromethane (2mL) was added 4-methylbenzenesulfonyl chloride (17.8mg, 0.09337mmol), triethylamine (30 μ L, 0.2152mmol) and a catalytic amount of N, N-lutidine-4-amine (2.7mg, 0.0221mmol). the reaction mixture was stirred at room temperature overnight. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated the resulting brown residue was purified by silica gel column chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate to give (14S) -4-methylbenzene-1-sulfonic acid 8- [3- (2- { dispiro [2.0.2.1 ] as a white solid]Hept-7-yl } (2, 2-dideuterio) ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2, 2, 4-trioxo-2 λ⁶-3, 9, 2, 3,11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-20-yl ester (36mg, 58%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.56(s, 1H), 8.20(d, J ═ 2.8Hz, 1H), 7.92(d, J ═ 8.4Hz, 2H), 7.80(d, J ═ 8.3Hz, 1H), 7.65(d, J ═ 8.1Hz, 1H), 7.47(d, J ═ 8.2Hz, 2H), 7.12(d, J ═ 8.1Hz, 1H), 6.91(d, J ═ 8.2Hz, 1H), 6.76(s, 1H), 6.08(d, J ═ 2.7 Hz, 1H), 4.20(d, J ═ 1.1Hz, 2H), 3.77(d, J ═ 13.2Hz, 1H), 3.34(m, 1H), 3.03(s, 1H), 2.79(d, J ═ 1.1H), 3.7 (d, J ═ 1.7H), 3.7H), 3.79 (d, J ═ 1H, 1.5 (d, 3.5H), 3.7H, 3.7 (d, 3.7H), 3.7H), 3.7H, 3.7 (d, 3.7H), 3.7, 4H) 0.68-0.59(M, 2H), 0.54-0.40(M, 2H). ESI-MS M/z Calculation 789.29474, Experimental value 690.18(M +1) ⁺(ii) a Retention time: 0.67min (LC method L).

And 5: (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } -2, 2-dideuterio-ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl (20-deuterium) -2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 298)

(14S) -4-methylbenzene-1-sulfonic acid 8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } (2, 2-dideuterio) ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2, 2, 4-trioxo-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]A solution of tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-20-yl ester (70mg, 0.088 mmol) in anhydrous N, N-dimethylformamide (2mL) was purged with nitrogen for 5min. Triphenylphosphane (15mg, 0.023mmol) and tricyclohexylphosphane (18mg, 0.064mmol). the resulting green solution was stirred under nitrogen atmosphere for 5min and tetradeuteroborate (sodium salt) (50mg, 1.195mmol) was added in one portionObject 1 h. Additionally adding nickel dichloride; triphenylphosphine (15mg, 0.023mmol), tricyclohexylphosphine (18mg, 0.064mmol) and tetradeuterium borate (sodium salt) (50mg, 1.195mmol) and the mixture was stirred at room temperature under nitrogen overnight the reaction mixture was diluted with water, extracted with ethyl acetate, the organic layer was dried over magnesium sulfate, filtered and evaporated. The resulting residue was dissolved in dimethyl sulfoxide and filtered through Whatman filter disc (puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS using a double gradient run of 50% -99% mobile phase B over 15.0min (mobile phase a ═ water (5mM hydrochloric acid), mobile phase B ═ acetonitrile) to give (14S) -8- [3- (2- { dispiro [2.0.2.1 ] as a white solid ]Hept-7-yl } -2, 2-dideuterio-ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl (20-deuterium) -2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 298) (22.8mg, 41%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.51(s, 1H), 8.20(d, J ═ 2.8Hz, 1H), 7.81(d, J ═ 8.3Hz, 1H), 7.57 (d, J ═ 7.3Hz, 1H), 7.05(d, J ═ 7.2Hz, 1H), 7.00(s, 1H), 6.91(d, J ═ 8.2Hz, 1H), 6.08(d, J ═ 2.7Hz, 1H), 4.20(d, J ═ 1.4Hz, 2H), 3.92(d, J ═ 12.4Hz, 1H), 3.16(s, 1H), 2.95(d, J ═ 13.2Hz, 1H), 2.71(t, J ═ 10.8Hz, 1H), 2.13(s, 1H), 1.86(d, J ═ 1.95 (d, J ═ 13.2Hz, 1H), 2.71(t, J ═ 10.8Hz, 1H), 1H, 2.13(s, 1H), 0.86 (s, 1H), 0.5H), 1.5 (s, 1H), 1H, 2H) in that respect ESI-MS M/z calculated 620.29, Experimental 621.24(M +1)⁺(ii) a Retention time: 1.3min (LC method J).

Example 104: preparation of (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl (20-deuterium) -2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 300)

Step 1: (14S) -4-methylbenzene-1-sulfonic acid 8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2, 2, 4-trioxo-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1- (23), 5, 7, 9, 19, 21-hexaen-20-yl esters

To (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-20-hydroxy-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]To a stirred solution of tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (150mg, 0.2367mmol) in anhydrous dichloromethane (3.000 mL) was added 4-methylbenzenesulfonyl chloride (58mg, 0.3042mmol), triethylamine (80. mu.L, 0.5740mmol), and a catalytic amount of N, N-dimethylpyridin-4-amine (10mg, 0.08185 mmol). The reaction mixture was stirred at room temperature overnight the reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The resulting brown residue was purified by silica gel column chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate to give (14S) -4-methylbenzene-1-sulfonic acid 8- [3- (2- { dispiro [2.0.2.1 ] as a white solid ]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2, 2, 4-trioxo-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-20-yl ester (120mg, 51%). ESI-MS M/z calculated 787.28217, Experimental 788.42(M +1)⁺(ii) a Retention time: 1.39min (LC method J).

Step 2: (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl (20-deuterium) -2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 300)

(14S) -4-methylbenzene-1-sulfonic acid 8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2, 2, 4-trioxo-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]A solution of tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-20-yl ester (120mg, 0.1523 mmol) in anhydrous N, N-dimethylformamide (1mL) was purged with nitrogen for 5min. Triphenylphosphine (30mg, 0.04586mmol) and tricyclohexylphosphine (34mg, 0.1212 mmol). the resulting green solution was stirred under nitrogen atmosphere for 5min, and tetradeuteroborate (sodium salt) (87mg, 2.079mmol) was added in one portion. Additionally adding nickel dichloride; triphenylphosphine (30mg, 0.04586mmol), tricyclohexylphosphine (34mg, 0.1212mmol) and tetradeuterium borate (sodium salt) (87mg, 2.079mmol), and the mixture was stirred at room temperature under nitrogen overnight. The reaction mixture was diluted with water and extracted with ethyl acetate the organic layer was dried over magnesium sulfate, filtered and evaporated the resulting residue was dissolved in dimethyl sulfoxide and filtered through Whatman filter disc (puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS using a double gradient run of 50% -99% mobile phase B over 15.0min (mobile phase a ═ water (5mM hydrochloric acid), mobile phase B ═ acetonitrile) to give (14S) -8- [3- (2- { dispiro [2.0.2.1 ]: white solid ]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl (20-deuterium) -2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 300) (35mg, 37%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.52(s，1H)，8.20(d，J＝2.8Hz，1H)，7.81(d，J＝8.2Hz，1H)，7.56 (d，J＝7.1Hz，1H)，7.04(d，J＝7.2Hz，1H)，6.98(s，1H)，6.90(d，J＝8.1Hz，1H)， 6.08(d，J＝2.7Hz，1H)，4.25-4.17(m，2H)，3.92(d，J＝12.5Hz，1H)，3.17(s，1H)， 2.94(d，J＝13.2Hz，1H)，2.72(s，1H)，2.20-2.06(m1H), 1.81(q, J ═ 6.6Hz, 4H), 1.60(s, 3H), 1.56(d, J ═ 13.5Hz, 2H), 1.51(s, 3H), 1.46(d, J ═ 6.5Hz, 1H), 1.36-1.26 (M, 1H), 1.23(s, 1H), 0.87-0.76(M, 4H), 0.70-0.59(M, 2H), 0.50(dd, J ═ 8.0, 4.3Hz, 2H), ESI-MS M/z calculated 618.2847, experimental value 619.25(M +1)⁺(ii) a Retention time: 1.28min (LC method J).

Example 105: preparation of (14S) -8- [3- (2- { dispiro [2.0.2.1]]Hept-7-yl } -1, 1, 2, 2-tetradeuterium-ethoxy) -1H-pyrazol-1-yl radical]-12, 12-dimethyl (20-deuterium) -2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaene-2, 2, 4-trione (compound 301)

Step 1: (4S) -4- [3- [ [ 3-benzyloxy-6- [ [ 2-chloro-6- [3- (1, 1, 2, 2-tetradeuterium-2-dispiro [2.0.2.1] hept-7-yl-ethoxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester.

To 2-chloro-6- [3- (1, 1, 2, 2-tetradeuterium-2-dispiro [2.0.2.1 ]]Hept-7-yl-ethoxy) pyrazol-1-yl]To a solution of pyridine-3-carboxylic acid (500mg, 1.374mmol) in anhydrous tetrahydrofuran (5mL) was added carbonyldiimidazole (207mg, 1.277mmol), and the mixture was stirred at room temperature for 2 h. Subsequently, (4S) -4- [3- [ (3-benzyloxy-6-sulfamoyl-2-pyridyl) amino group is added]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (410mg, 0.7905mmol) followed by addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (600 μ L, 4.012mmol) and the reaction stirred at room temperature for 14hThe resulting brown residue was purified in a gentle gradient to give (4S) -4- [3- [ [ 3-benzyloxy-6- [ [ 2-chloro-6- [3- (1, 1, 2, 2-tetradeuterium-2-dispiro [2.0.2.1 ]) as an off-white foamy solid]Hept-7-yl-ethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (436g, 37%). ESI-MS calculated M/z 863.3745, Experimental 864.47 (M +1) ⁺(ii) a Retention time: 1.74min (LC method L).

Step 2: (14S) -20- (benzyloxy) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } -1, 1, 2, 2-tetradeuterium-ethoxy) -1H-pyrazol-1-yl radical]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione

(4S) -4- [3- [ [ 3-benzyloxy-6- [ [ 2-chloro-6- [3- (1, 1, 2, 2-tetradeuterium-2-dispiro [2.0.2.1 ]) is reacted at room temperature]Hept-7-yl-ethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]A solution of tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (436g, 0.5043mmol) in trifluoroacetic acid (400 μ L, 5.192mmol) and dichloromethane (1.6mL) was stirred for 2h the solvent was evaporated and the resulting residue was dissolved in ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate (2mL) and the organic layer was collected and the solvent was removed. The resulting residue was dissolved in dimethyl sulfoxide (5mL) and oven dried

MS and stir the resulting mixture for 10 min. Subsequently, potassium carbonate (231mg, 1.671mmol) was added and the reaction mixture was heated at 140 ℃ for 16h, filtered through Whatman filter disc (puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS using a double gradient run of 50% -99% mobile phase B over 15.0min (mobile phase a ═ water (5 mM hydrochloric acid), mobile phase B ═ acetonitrile) to give (14S) -20- (benzyloxy) -8- [3- (2- { dispiro [2.0.2.1 ═ acetonitrile) as an off-white solid ]Hept-7-yl} -1, 1, 2, 2-tetradeuterium-ethoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (184mg, 44%).¹H NMR (400MHz, chloroform-d) 9.96(s, 1H), 8.19(d, J ═ 2.8Hz, 1H), 8.06(d, J ═ 8.4Hz, 1H), 7.55(d, J ═ 8.0Hz, 1H), 7.46-7.36(m, 5H), 7.27(d, J ═ 8.5Hz, 1H), 7.00(d, J ═ 8.1Hz, 1H), 5.90(d, J ═ 2.8Hz, 1H), 5.32(d, J ═ 6.3Hz, 1H), 5.11(s, 2H), 3.91(s, 1H), 3.42-3.31(m, 1H), 3.19(d, J ═ 14.1Hz, 1H), 3.05(t, J ═ 9.7, 1H), 3.42-3.31(m, 1H), 3.19(d, J ═ 14.1Hz, 1H), 3.05(t, J ═ 9, 1H), 2, 1H), 3.69 (H, 2H), 3.85 (H, 1H, 2H), 3.7, 1H, 2H), 3.6, 1H, 62, 1H, 2H, 1H, 2H) 0.54-0.46(m, 2H). ESI-MS M/z calculated 727.3454, Experimental 728.47(M +1)⁺(ii) a Retention time: 1.43min (LC method J).

And step 3: (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } -1, 1, 2, 2-tetradeuterium-ethoxy) -1H-pyrazol-1-yl radical]-20-hydroxy-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione

To (14S) -20- (benzyloxy) -8- [3- (2- { dispiro [2.0.2.1 ] under nitrogen]Hept-7-yl } -1, 1, 2, 2-tetradeuterium-ethoxy) -1H-pyrazol-1-yl radical]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]A stirred solution of tetracos-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (184mg, 0.2528mmol) in EtOH (5mL) was added 10% palladium on carbon (moist, Degussa, 27 mg, 0.02537mmol), the heterogeneous mixture was stirred under hydrogen (from a balloon) at ambient temperature for about 2h, and the black heterogeneous reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give (14S) -8- [3- (2- { dispiro [2.0.2.1 ] as a pale brown solid]Hept-7-yl } -1, 1, 2, 2-tetradeuterium-ethoxy) -1H-pyrazol-1-yl radical]-20-hydroxy-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (160mg, 83%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.42(s, 1H), 11.02(s, 1H), 8.30(d, J ═ 2.7Hz, 1H), 7.86(d, J ═ 8.2Hz, 1H), 7.17(d, J ═ 7.7Hz, 1H), 7.06(d, J ═ 7.8Hz, 1H), 7.00(d, J ═ 8.2Hz, 1H), 6.27(s, 1H), 6.18(d, J ═ 2.8Hz, 1H), 4.01(s, 1H), 3.28(s, 1H), 3.09(d, J ═ 12.9Hz, 1H), 2.86-2.69(m, 1H), 2.22(s, 1H), 2.01(s, 1H), 1.99-1.90(m, 1H), 1.65(d, 1H), 1.34 (d, 1H), 0.7.7H, 1H), 0.7 (m, 0.7H), 0.7H, 1H, 0.7H, 1H, 0.9H, 0.7H, 1H, 0.7H, 0, 0.7H, 1H, 0, and 0H. ESI-MS M/z calculated 637.29846, Experimental 638.33(M +1) ⁺(ii) a Retention time: 0.91min (LC method J).

And 4, step 4: (14S) -4-methylbenzene-1-sulfonic acid 8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } -1, 1, 2, 2-tetradeuterium-ethoxy) -1H-pyrazol-1-yl radical]-12, 12-dimethyl-2, 2, 4-trioxo-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1- (23), 5, 7, 9, 19, 21-hexaen-20-yl esters

To (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } -1, 1, 2, 2-tetradeuterium-ethoxy) -1H-pyrazol-1-yl radical]-20-hydroxy-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]To a stirred solution of tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (160mg, 0.2107mmol) in anhydrous dichloromethane (2mL) was added 4-methylbenzenesulfonyl chloride (45mg, 0.2360mmol), triethylamine (60. mu.L, 0.4305mmol), and a catalytic amount of N, N-dimethylpyridin-4-amine (6mg, 0.04911 mmol). The reaction mixture was stirred at room temperature overnight the reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. Salt organic layerThe resulting brown residue was purified by silica gel column chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate to give (14S) -4-methylbenzene-1-sulfonic acid 8- [3- (2- { dispiro [2.0.2.1 ] as a white solid ]Hept-7-yl } -1, 1, 2, 2-tetradeuterium-ethoxy) -1H-pyrazol-1-yl radical]-12, 12-dimethyl-2, 2, 4-trioxo-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-20-yl ester (147mg, 88%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.51(s, 1H), 8.14(s, 1H), 7.85(d, J ═ 8.2Hz, 2H), 7.73(d, J ═ 8.2Hz, 1H), 7.59(d, J ═ 8.0Hz, 1H), 7.41(d, J ═ 8.2Hz, 2H), 7.05(d, J ═ 8.0Hz, 1H), 6.84(d, J ═ 8.2Hz, 1H), 6.70(s, 1H), 6.02(d, J ═ 2.7Hz, 1H), 3.76-3.64 (m, 1H), 3.24(d, J ═ 7.0Hz, 1H), 2.96(tt, J ═ 11.8, 5.3Hz, 1H), 2.73(d, J ═ 13.2, 1H, 2, 1H), 11.35 (s, 1H), 1H, 12.19 (t, 12.6.6.6, 1H), 1H, 5.3.3H, 1H, 2.5.3H, 1H, 2.3H, 12 (t ═ 2, 12, 2, 5.6, 2, 1H, 2, 1H, j ═ 3.5Hz, 4H), 0.57(dd, J ═ 8.1, 4.4Hz, 2H), 0.43(d, J ═ 9.2Hz, 2H.) ESI-MS M/z calculated 791.3073, experimental 792.17(M +1)⁺(ii) a Retention time: 0.65min (LC method L).

And 5: (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } -1, 1, 2, 2-tetradeuterium-ethoxy) -1H-pyrazol-1-yl radical ]-12, 12-dimethyl (20-deuterium) -2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaene-2, 2, 4-trione (compound 301)

(14S) -4-methylbenzene-1-sulfonic acid 8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } -1, 1, 2, 2-tetradeuterium-ethoxy) -1H-pyrazol-1-yl radical]-12, 12-dimethyl-2, 2, 4-trioxo-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Twenty-four carbon-1 (23) A solution of 5, 7, 9, 19, 21-hexaen-20-yl ester (145mg, 0.1831mmol) in anhydrous N, N-dimethylformamide (2mL) was purged with nitrogen for 5min then nickel dichloride was added; triphenylphosphane (42mg, 0.06420mmol) and tricyclohexylphosphane (46mg, 0.1640 mmol.) the resulting green solution was stirred under a nitrogen atmosphere for 5min and tetradeuteroborate (sodium salt) (108mg, 2.580mmol) was added in one portion. The resulting dark reddish brown mixture was stirred at room temperature for 1 h. Additionally adding nickel dichloride; triphenylphosphine (42mg, 0.06420mmol), tricyclohexylphosphine (46mg, 0.1640mmol) and tetradeuteroborate (sodium salt) (108mg, 2.580mmol) and the mixture was stirred under nitrogen overnight at room temperature the reaction mixture was diluted with water, extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated the resulting residue was dissolved in dimethyl sulfoxide and filtered through Whatman filter disc (puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS using a double gradient run of 50% -99% mobile phase B over 15.0min (mobile phase a ═ water (5mM hydrochloric acid). mobile phase B ═ acetonitrile) to give (14S) -8- [3- (2- { dispiro [2.0.2.1 ═ acetonitrile) as a white solid ]Hept-7-yl } -1, 1, 2, 2-tetradeuterium-ethoxy) -1H-pyrazol-1-yl radical]-12, 12-dimethyl (20-deuterium) -2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 301) (26.9mg, 24%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.60(s, 1H), 8.30(d, J ═ 2.8Hz, 1H), 7.91(d, J ═ 8.2Hz, 1H), 7.70-7.66 (m, 1H), 7.15(d, J ═ 7.2Hz, 1H), 7.08(d, J ═ 8.9Hz, 1H), 7.01(d, J ═ 8.2Hz, 1H), 6.18(d, J ═ 2.7Hz, 1H), 4.02(d, J ═ 12.1Hz, 1H), 3.26(d, J ═ 6.9Hz, 1H), 3.05 (d, J ═ 13.2Hz, 1H), 2.83-2.76(m, 1H), 2.20(d, J ═ 19.9Hz, 1H), 1.99 (d, J ═ 13.2Hz, 1H), 1H, 0.70H, 0.7 (m, 1H), 1H, 5 (m, 1H), 5 (m, 1H, 0.70H, 0.7H, 1, experimental value 623.26(M +1)⁺(ii) a Retention time: 1.3min (LC method J).

Example 106: preparation of 11- [3- (2, 2-dimethylpropoxy) -1H-pyrazol-1-yl]-7, 7-dimethyl-17. lambda.⁶- Thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14 ]Tricosane-1 (21), 9(14), 10, 12, 18(22), 19-hexaene-15, 17, 17-trione (Compound 1)

Step 1: 1-benzyl-5, 5-dimethylpyrrolidin-2-one

5, 5-Dimethylpyrrolidin-2-one (19.6g, 0.174mol) was dissolved in N, N-dimethylformamide (100 ml) and cooled to 0 ℃, followed by slow addition of NaH (10.4g, 0.261 mol). The reaction mixture was stirred for 10min, after which benzyl chloride (22mL, 0.19mol) was added, the reaction mixture was warmed to 21 ℃ over a period of 16 h. By addition of NH₄The reaction was quenched by the addition of ethyl acetate, the layers were separated, and the aqueous layer was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by rapid filtration through a silica gel pad (20% ethyl acetate/heptane) to give pure 1-benzyl-5, 5-dimethylpyrrolidin-2-one as a colorless oil (30g, 85%).¹H NMR(300MHz，CDCl₃)：7.3(m，5H)；4.4(s，2H)；2.42(t，2H)；1.9(t，2H)；1.1(s， 6H)。

Step 2: 1-benzyl-5, 5-dimethyl-2-oxopyrrolidine-3-carboxylic acid ester

Diisopropylamine (27.6mL, 197mmol) was dissolved in tetrahydrofuran (200mL) under a nitrogen atmosphere and cooled to-78 ℃. n-BuLi (79mL, 197mmol, 2.5M solution in hexane) was added dropwise and stirring continued for a further 90min while warming to-20 ℃. the reaction mixture was cooled again to-78 ℃ and 1-benzyl-5, 5-dimethylpyrrolidin-2-one (20g, 98.4mmol) dissolved in tetrahydrofuran (20mL) was added while maintaining the temperature below-78 deg.C stirring was continued for an additional 1h, at which time the temperature was corrected to-80 deg.C and dimethyl carbonate (17.4mL, 206.6mmol) was added and the reaction mixture was allowed to warm to-20 deg.C. Water (20mL) was added slowly followed by 4N aqueous hydrochloric acid (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2X 20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated after purification by silica gel chromatography (40% ethyl acetate/heptane) to give pure methyl 1-benzyl-5, 5-dimethyl-2-oxopyrrolidine-3-carboxylate (7.8g, 30%) as a yellow oil.¹H NMR(300MHz，CDCl₃)：d 7.3(m， 5H)；4.4(dd，2H)；3.8(s，3H)；3.6(t，1H)；2.2(m，2H)；1.2(s，3H)；1.1(s，3H).

And step 3: 2- (1-benzyl-5, 5-dimethylpyrrolidin-3-yl) acetonitrile

Lithium aluminum hydride (4.2g, 110.4mmol) was suspended in tetrahydrofuran (100mL) and cooled to 0 deg.C, followed by dropwise addition of methyl 1-benzyl-5, 5-dimethyl-2-oxopyrrolidine-3-carboxylate (7.8g, 29.8mmol) dissolved in tetrahydrofuran (20 mL). The reaction mixture was warmed to 20 ℃ over a period of 16h, quenched with water and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over sodium sulfate and concentrated crude (1-benzyl-5, 5-dimethylpyrrolidin-3-yl) methanol (6.6g, quantitative) was used in the next step without further purification. ¹H NMR(300MHz，CDCl₃)：d 7.3(m，5H)；3.8(d，1H)；3.5(m，2H)；3.2(d，1H)； 2.8(bs，1H)；2.6(m，2H)；2.2(m，1H)；1.9(m，1H)；1.6(m，1H)；1.3(s，3H)；1.03(s， 3H)。

And 4, step 4: 2- (1-benzyl-5, 5-dimethylpyrrolidin-3-yl) acetonitrile

(1-benzyl-5, 5-dimethylpyrrolidin-3-yl) methanol (5g, 22.8mmol) was dissolved in tetrahydrofuran (60mL) and cooled to-23 deg.C, then Et3N (4.74mL, 34.2mmol) and MsCl (2.1 mL, 27.4mmol) were added, the reaction mixture was stirred at this temperature for 15min, then the cooling bath was removed, and stirring was continued for an additional 30min. The layers were separated and the aqueous layer was washed with ethyl acetate (2X 30 mL). The combined organic layers were dried over sodium sulfate and concentrated the crude material was further dissolved in dimethylsulfoxide (40mL) and sodium cyanide (1.7g, 34.2mmol) was added the residue was stirred at 60 ℃ for 5h, after which another amount of sodium cyanide (770mg) was added and stirring was continued for 5h again the reaction mixture was cooled, water was added, after which ethyl acetate was added the layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 20mL), the combined organic layers were dried over sodium sulfate and concentrated after purification by silica gel chromatography (30% ethyl acetate/heptane) pure 2- (1-benzyl-5, 5-dimethylpyrrolidin-3-yl) acetonitrile was obtained as a yellow oil (3g, 58%).¹H NMR (300MHz，CDCl₃)：d 7.3(m，5H)；3.7(d，1H)；3.4(d，1H)；2.78(t，1H)；2.4(m，2H)； 2.0(m，1H)；1.6(m，2H)；1.2(s，3H)；1.05(s，3H)。

And 5: 2- (1-benzyl-5, 5-dimethylpyrrolidin-3-yl) ethan-1-amine hydrochloride

Lithium aluminum hydride (1.25g, 32.8mmol) was suspended in tetrahydrofuran (30mL) and cooled to 0 ℃, followed by slow addition of 2- (1-benzyl-5, 5-dimethylpyrrolidin-3-yl) acetonitrile (3g, 13.1mmol) dissolved in tetrahydrofuran (5mL) and warming of the reaction mixture to 20 ℃ over a period of 15 h. The reaction was quenched with water (20mL) and 15% aqueous sodium hydroxide (10 mL). The resulting precipitate was filtered through a pad of celite. The filter cake was washed with ethyl acetate and the layers were separated. The organic layer containing the crude amine was concentrated and the residue was treated with 4N hydrochloric acid in dioxane, followed by evaporation to give pure 2- (1-benzyl) as a yellowish solid-5, 5-Dimethylpyrrolidin-3-yl) ethan-1-amine hydrochloride (3.8g, 98%). 1H NMR (300MHz, D₂O): d 7.4(m, 5H); 4.4 (m, 1H); 3.9(m, 1H); 3.6(m, 1H); 3.4 and 3.0(m, 1H); 2.8(m, 2H); 2.6(m, 1H); 2.2 (m, 1H); 1.6(m, 1H); 1.42(s, 3H); 1.3(s, 3H).

Step 6: 2- (5, 5-dimethylpyrrolidin-3-yl) ethan-1-amine dihydrochloride

To a solution of 2- (1-benzyl-5, 5-dimethylpyrrolidin-3-yl) ethan-1-amine hydrochloride (1g, 3.720mmol) in methanol (10mL) was added palladium hydroxide (653.0mg, 0.9300mmol) and hydrochloric acid (155.0 μ L6M hydrochloric acid, 0.9300mmol), the reaction flask was evacuated and rinsed with H2 using a balloon with a three-way adapter and repeated 3 times, the reaction mixture was stirred at room temperature for 48H under an atmosphere of H2, the bed was filtered through a bed of celite, and washed with methanol, the filtrate was evaporated to give 2- (5, 5-dimethylpyrrolidin-3-yl) dihydrochloride (557mg, 70%). ESI-MS M/z calculated 142.147, experimental 143.2(M +1) ⁺(ii) a Retention time: 0.09min (LC method A).

And 7: 3- (2, 2-dimethylpropoxy) pyrazole-1-carboxylic acid tert-butyl ester

To 3-hydroxypyrazole-1-carboxylic acid tert-butyl ester (40g, 217.2mmol) in tetrahydrofuran (480.0 mL) under nitrogen was added 2, 2-dimethylpropan-1-ol (21.06g, 238.9mmol) and triphenylphosphine (62.66g, 55.35 mL, 238.9mmol). to the mixture was added dropwise DIAD (48.31g, 47.04mL, 238.9mmol) and the mixture was gradually allowed to exotherm to 45 ℃. After addition, the mixture was heated at 50 ℃ for 5h then the mixture was cooled to ambient temperature the reaction mixture was diluted with 200mL ethyl acetate and the organic phase was washed with 500mL 1N sodium hydroxide, 500mL brine, dried over magnesium sulfate, filtered through celite, and concentrated in vacuo to a volume of about 300mLThe phosphine oxide based crystallization started and the light red slurry was allowed to stand overnight the slurry was filtered using a medium pore glass frit and washed 3 x with 100mL of 50% ethyl acetate/hexane. The filtrate was concentrated in vacuo. The crude pink oil was diluted with dichloromethane and subjected to 750g of silica gel column chromatography eluting with a 0-25% ethyl acetate/hexane gradient, 330g of silica gel column re-chromatography of the collected impure fractions eluting with 0-25% ethyl acetate/hexane, the pure fractions from both columns were combined and concentrated to give tert-butyl 3- (2, 2-dimethylpropoxy) pyrazole-1-carboxylate (45.8g, 83%). ¹H NMR (400MHz, chloroform-d) 7.83(d, J ═ 3.2Hz, 1H), 5.88(d, J ═ 3.2Hz, 1H), 3.95(s, 2H), 1.62(d, J ═ 2.2Hz, 9H), 1.01(d, J ═ 2.7Hz, 9H), ESI-MS M/z calculated 254.16304, experimental 199.1(M +1-^tBu)⁺(ii) a Retention time: 1.89min (LC method B).

And 8: 3- (2, 2-dimethylpropoxy) -1H-pyrazole

To dichloromethane (450mL) containing tert-butyl 3- (2, 2-dimethylpropoxy) pyrazole-1-carboxylate (111g, 436.4mmol) and methanol (450mL) was added hydrochloric acid (330mL 4M in dioxane, 1.320mol) (gradual exotherm to about 35 ℃), and the mixture was stirred at 45 ℃ for 1H the solvent was removed in vacuo, and the residue was diluted with MTBE (900 mL) and washed with sodium hydroxide (650mL, 2M, 1.300mol), the aqueous phase was extracted with 500mL MTBE, and the combined organic phases were washed with 800mL brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 3- (2, 2-dimethylpropoxy) -1H-pyrazole as an off-white solid (65g, 97%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)11.81(s, 1H), 7.48(d, J ═ 2.5Hz, 1H), 5.65(t, J ═ 1.9Hz, 1H), 3.70(s, 2H), 0.96(s, 9H), ESI-MS M/z calculated 154.11061, experimental 155.1 (M +1)⁺(ii) a Retention time: 1.48min (LC method D).

And step 9: 2-chloro-6- [3- (2, 2-dimethylpropoxy) pyrazol-1-yl ] pyridine-3-carboxylic acid tert-butyl ester

To N, N-dimethylformamide (95.10mL) containing tert-butyl 2, 6-dichloropyridine-3-carboxylate (12.75g, 51.39mmol) and 3- (2, 2-dimethylpropoxy) -1H-pyrazole (7.925g, 51.39mmol) was added potassium carbonate (9.232g, 66.80mmol) and 1, 4-diazabicyclo [2.2.2 mmol) under nitrogen]Octane (864.6mg, 7.708 mmol) and the reaction stirred at room temperature for 18h the milky fine suspension was diluted with water (95.10mL) to allow precipitation of a gum that started to solidify. The mixture was allowed to stand and the clear solution was decanted from the gummy solid. The solid was diluted with 200 mL of water and 25mL of isopropanol. The mixture was heated until the solution became homogeneous. The mixture was allowed to cool and then placed in an ice bath to give a creamy yellow semi-solid. The solid was collected using a medium pore frit and washed 3X with 10mL water, the solid was air dried for 18h to afford 2-chloro-6- [3- (2, 2-dimethylpropoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (18g, 95%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)8.41(d, J ═ 2.9Hz, 1H), 8.30(d, J ═ 8.4Hz, 1H), 7.73(d, J ═ 8.4Hz, 1H), 6.22(d, J ═ 2.9Hz, 1H), 3.92(s, 2H), 1.57(s, 9H), 1.01(s, 9H). ESI-MS M/z calculated 365.1506, Experimental 366.2(M +1) ⁺(ii) a Retention time: 3.53min (LC method D).

Step 10: 2-chloro-6- [3- (2, 2-dimethylpropoxy) pyrazol-1-yl ] pyridine-3-carboxylic acid

To a solution containing 2-chloro-6- [3- (2, 2-dimethylpropoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (18g, 49.20 mmol) in isopropanol (90.00mL) aqueous hydrochloric acid (41.00mL, 6M, 246.0mmol) was added and the mixture was heated to reflux for 90min (oil bath temperature 100 ℃). the mixture was cooled to ambient temperature and then diluted with water (90.00 mL.) the slurry was cooled slightly with an ice water bath and the precipitate was collected using a medium pore glass frit, the precipitate was washed 3 x with 10mL water and vacuum at 45 ℃Drying for 2 days to obtain 2-chloro-6- [3- (2, 2-dimethylpropoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (12.72g, 83%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)13.62(s, 1H), 8.42(d, J ═ 2.9Hz, 1H), 8.38(d, J ═ 8.4Hz, 1H), 7.74(d, J ═ 8.4Hz, 1H), 6.22(d, J ═ 2.9Hz, 1H), 3.93(s, 2H), 1.01(s, 9H). ESI-MS M/z calculated 309.088, Experimental 310.2(M +1)⁺(ii) a Retention time: 2.61min (LC method D).

Step 11: 2-chloro-6- [3- (2, 2-dimethylpropoxy) pyrazol-1-yl ] -N- [ (6-fluoro-2-pyridinyl) sulfonyl ] pyridine-3-carboxamide

A40 mL vial was charged with 2-chloro-6- [3- (2, 2-dimethylpropoxy) pyrazol-1-yl under nitrogen]Pyridine-3-carboxylic acid (1.0g, 3.228mmol) and carbonyldiimidazole (785.1mg, 4.842 mmol.) N, N-dimethylformamide (9.615mL) was added and the mixture was stirred at 45 ℃ under nitrogen for 1 h. In a separate 40mL vial, a solution of 6-fluoro-2-pyridinesulfonamide (682.5mg, 3.874mmol) was dissolved in anhydrous N, N-dimethylformamide (9.615mL) under nitrogen, sodium hydride (154.9mg, 3.874mmol) (60% oily suspension) was added portionwise, and the mixture was stirred under nitrogen until gas evolution ceased. The vial was capped and stirred at 45 ℃ for 45 min. The two mixtures were combined and stirred at room temperature for 2 h. Water and ice were added. Concentrated hydrochloric acid was added dropwise until a white precipitate remained, followed by washing with ethyl acetate (2 ×), the organic layers were combined, dried (sodium sulfate), filtered and concentrated to a yellow residue. The residue was dissolved in ethyl acetate and washed with 1: 1 saturated aqueous sodium bicarbonate/1N sodium hydroxide (3X), dried over sodium sulfate, filtered and concentrated the material was further purified by silica gel chromatography using a gradient of 100% hexane to 100% ethyl acetate to isolate 2-chloro-6- [3- (2, 2-dimethylpropoxy) pyrazol-1-yl as a pale yellow foam ]-N- [ (6-fluoro-2-pyridyl) sulfonyl group]Pyridine-3-carboxamide (1.01g, 67%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)8.36(d， J＝2.8Hz, 1H), 8.21-8.10(M, 2H), 7.89(d, J ═ 5.7Hz, 1H), 7.65(d, J ═ 8.3Hz, 1H), 7.30(d, J ═ 7.1Hz, 1H), 6.15(d, J ═ 2.8Hz, 1H), 3.92(s, 2H), 1.00(s, 9H) ESI-MS M/z calculated 467.08304, experimental 468.2(M +1)⁺(ii) a Retention time: 1.92min (LC method E).

Step 12: 11- [3- (2, 2-Dimethylpropyloxy) -1H-pyrazol-1-yl radical]-7, 7-dimethyl-17. lambda.⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosane-1 (21), 9(14), 10, 12, 18(22), 19-hexaene-15, 17, 17-trione (Compound 1)

Combine 2-chloro-6- [3- (2, 2-dimethylpropoxy) pyrazol-1-yl in a 5mL vial]-N- [ (6-fluoro-2-pyridyl) sulfonyl group]Pyridine-3-carboxamide (330mg, 0.6065mmol) in dimethylsulfoxide (2.980mL), potassium carbonate (419.2mg, 3.033mmol) and 2- (5, 5-dimethylpyrrolidin-3-yl) ethylamine dihydrochloride (108.4mg, 0.504 mmol). The vial was capped and heated to 120 ℃ on a hot plate for 20 h. 2- (5, 5-dimethylpyrrolidin-3-yl) ethylamine dihydrochloride (108.4mg, 0.504mmol) was additionally added and heated to 125 ℃ on a hot plate for 24 h. The reaction mixture was filtered and then chromatographed by reverse-phase preparative chromatography using C ₁₈Column (10-99% acetonitrile-water +5mM hydrochloric acid) directly purified to give an off-white solid to which excess potassium carbonate (419.2mg, 3.033mmol) and dimethyl sulfoxide (2.980mL) were added and the mixture heated at 155 ℃ for 18 h. The reaction mixture was filtered and then chromatographed by reverse-phase preparative chromatography using C₁₈Direct purification on a column (10-99% acetonitrile-water +5mM hydrochloric acid) to give 11- [3- (2, 2-dimethylpropoxy) -1H-pyrazol-1-yl as a pale yellow solid, as the more polar regioisomer]-7, 7-dimethyl-17. lambda.⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosane-1 (21), 9(14), 10, 12, 18(22), 19-hexaen-15, 17, 17-trione (compound 1) (34.5mg, 10%).¹H NMR (400MHz, two methanol)Sulfoxide-d₆)12.45(s, 1H), 8.27-8.16(M, 1H), 7.74(d, J ═ 30.7 Hz, 2H), 7.17(d, J ═ 6.1Hz, 1H), 6.96-6.88(M, 1H), 6.88-6.74(M, 1H), 6.17-6.10 (M, 1H), 3.89(s, 2H), 3.61(dd, J ═ 15.1, 8.4Hz, 1H), 3.35(s, 1H), 2.48-2.29(M, 1H), 2.25(s, 1H), 1.91(dd, J ═ 10.8, 5.3Hz, 2H), 1.56(s, 6H), 1.50(s, 1H), 1.43-1.28 (M, 1H), 1.19 (J ═ 10.8, 5.3Hz, 2H), 1.56(s, 6H), 1.50(s, 1H), 1.43-1.28 (M, 1H), 19(dd, 7.8, 9.84), experimental values (M, 1H), 1H, 2H), and calculated values (M, 1H) ⁺(ii) a Retention time: 2.14min (LC method E).

Example 107: preparation of 11- [3- (2, 2-dimethylpropoxy) -1H-pyrazol-1-yl]-7, 7-dimethyl-17. lambda.⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosane-1 (21), 9(14), 10, 12, 18(22), 19-hexaen-15, 17, 17-trione (enantiomer 1) (compound 2) and 11- [3- (2, 2-dimethylpropoxy) -1H-pyrazol-1-yl]-7, 7-dimethyl-17. lambda.⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosane-1 (21), 9(14), 10, 12, 18(22), 19-hexaene-15, 17, 17-trione (enantiomer 2) (compound 3)

Step 1: 11- [3- (2, 2-Dimethylpropyloxy) -1H-pyrazol-1-yl radical]-7, 7-dimethyl-17. lambda.⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosane-1 (21), 9(14), 10, 12, 18(22), 19-hexaen-15, 17, 17-trione (enantiomer 1) (compound 2) and 11- [3- (2, 2-dimethylpropoxy) -1H-pyrazol-1-yl]-7, 7-dimethyl-17. lambda.⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosane-1 (21), 9(14), 10, 12, 18(22), 19-hexaene-15, 17, 17-trione (enantiomer 2) (compound 3)

Racemic 11- [3- (2, 2-dimethylpropoxy) -1H-pyrazol-1-yl was treated with ChiralPak AS-H (250X 10mm column, 5 μm particle size) and a 28% methanol/72% carbon dioxide mobile phase (10mL/min)]-7, 7-dimethyl-17. lambda.⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosane-1 (21), 9(14), 10, 12, 18(22), 19-hexaen-15, 17, 17-trione (28.4mg) for chiral SFC purification to give 11- [3- (2, 2-dimethylpropoxy) -1H-pyrazol-1-yl as the first enantiomer to be eluted]-7, 7-dimethyl-17. lambda.⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosane-1 (21), 9(14), 10, 12, 18(22), 19-hexaen-15, 17, 17-trione (enantiomer 1) (Compound 2) (4.4 mg, 32%), ESI-MS M/z calculated 553.24713, experimental 554.2(M +1)⁺(ii) a Retention time: 2.14 min (LC method E); and 11- [3- (2, 2-dimethylpropoxy) -1H-pyrazol-1-yl as the second enantiomer to be eluted]-7, 7-dimethyl-17. lambda.⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosane-1 (21), 9(14), 10, 12, 18(22), 19-hexaen-15, 17, 17-trione (enantiomer 2) (compound 3) (5.6mg, 41%), ESI-MS M/z calculated 553.24713, experimental 554.2(M +1) ⁺(ii) a Retention time: 2.15min (LC method E).

Example 108: preparation of 7, 7-dimethyl-11- (3- { [1- (trifluoromethyl) cyclopropyl]Methoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.1(5, 8).0(9, 14)]Tricosane-1 (21), 9(14), 10, 12, 18(22), 19-hexaene-15, 17, 17-trione (Compound 4)

Step 1: 2-chloro-N- [ (6-fluoro-2-pyridyl) sulfonyl ] -6- [3- [ [1- (trifluoromethyl) cyclopropyl ] methoxy ] pyrazol-1-yl ] pyridine-3-carboxamide

2-chloro-6- [3- [ [1- (trifluoromethyl) cyclopropyl ] at 60 deg.C]Methoxy radical]Pyrazol-1-yl]A solution of pyridine-3-carboxylic acid (3.5 g, 9.386mmol) and carbonyldiimidazole (2.283g, 14.08mmol) in dimethylformamide (32.64mL) was stirred for 60min, and a separate solution of 6-fluoro-2-pyridinesulfonamide (1.984g, 11.26mmol) and sodium hydride (450.4mg, 11.26mmol) in dimethylformamide (32.64mL) was stirred at 45 ℃ for 45 min. Cooled to room temperature and poured into water. Concentrated hydrochloric acid was added dropwise until a white precipitate remained, followed by washing with ethyl acetate (2 ×), the organic layers were combined, dried (sodium sulfate), filtered and concentrated to a white solid, dissolved in ethyl acetate and washed with 1: 1 saturated aqueous sodium bicarbonate/1N sodium hydroxide (3 ×), dried (sodium sulfate), filtered and concentrated to an off-white foam. The residue was dissolved in a minimum amount of warm dichloromethane, left to stand for 5min, then cooled to 4 ℃ overnight, the white solid cake was filtered and washed with dichloromethane. The filtrate was concentrated to a yellow solid, dissolved in a minimum amount of warm dichloromethane and slowly cooled to 4 ℃ overnight the resulting white solid cake was filtered and washed with dichloromethane to give 2-chloro-N- [ (6-fluoro-2-pyridinyl) sulfonyl ]-6- [3- [ [1- (trifluoromethyl) cyclopropyl ] group]Methoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (3.339g, 62%). ESI-MS M/z calculated 519.86, experimental 520.2(M +1)⁺(ii) a Retention time: 1.75min (LC method B).

Step 2: 7, 7-dimethyl-11- (3- { [1- (trifluoromethyl) cyclopropyl]Methoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.1(5, 8).0(9, 14)]Tricosane-1 (21), 9(14), 10, 12, 18(22), 19-hexaene-15, 17, 17-trione (Compound 4)

Combine 2-chloro-N- [ (6-fluoro-2-pyridyl) sulfonyl-containing group in a 5mL vial]-6- [3- [ [1- (trifluoromethyl) cyclopropyl ] group]Methoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (400mg, 0.7310mmol) in dimethylsulfoxide (3.040 mL), followed by potassium carbonate (505.1mg, 3.655mmol) and 2- (5, 5-dimethylpyrrolidin-3-yl) ethylamine dihydrochloride (137.2mg, 0.64mmol). the vial was capped and heated to 75 ℃ on a hot plate for 92h, followed by heating at 125 ℃ for 20 h. The reaction mixture was filtered and then chromatographed by reverse-phase preparative chromatography using C₁₈Column (10-99% acetonitrile-water +5mM hydrochloric acid) direct purification to give the product 7, 7-dimethyl-11- (3- { [1- (trifluoromethyl)) cyclopropyl-alcohol isolated as a tan solid ]Methoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.1(5, 8).0(9, 14)]Tricosane-1 (21), 9(14), 10, 12, 18(22), 19-hexaen-15, 17, 17-trione (compound 4) (35.2mg, 9%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.43(s, 1H), 8.43-8.41(m, 1H), 8.21(d, J ═ 2.8Hz, 1H), 7.74(d, J ═ 33.4Hz, 2H), 7.17(d, J ═ 7.0Hz, 1H), 6.91(d, J ═ 8.2Hz, 1H), 6.82(s, 1H), 6.15(d, J ═ 2.7Hz, 1H), 4.37(q, J ═ 11.9Hz, 2H), 3.61(d, J ═ 9.1Hz, 1H), 3.41 (d, J ═ 3.9Hz, 1H), 3.19(d, J ═ 26.6Hz, 2H), 2.26(d, J ═ 5.9, 1H), 1.91(d, J ═ 3.5, 1H), 1.6H, 1H, 11.26 (d, 1H), 1.6H, 11.19 (d, 1H), 11.06, 11.6H), 11.6H, 11.8 (d, 1H), 1H, 1. ESI-MS M/z calculated 605.2032, Experimental 606.2 (M +1)⁺(ii) a Retention time: 2.02min (LC method E).

Example 109: preparation of 7, 7-dimethyl-11- (3- { [1- (trifluoromethyl) cyclopropyl]Methoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.1(5, 8).0(9, 14)]Tricosane-1 (21), 9(14), 10, 12, 18(22), 19-hexaen-15, 17, 17-trione (enantiomer 1) (compound 5) and 7, 7-dimethyl-11- (3- { [1- (trifluoromethyl) cyclopropyl ]Methoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.1(5, 8).0(9, 14)]Tricosane-1 (21), 9(14), 10, 12, 18(22), 19-hexaene-15, 17, 17-trione (enantiomer 2) (compound 6)

Step 1: 7, 7-dimethyl-11- (3- { [1- (trifluoromethyl) cyclopropyl]Methoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.1(5, 8).0(9, 14)]Tricosane-1 (21), 9(14), 10, 12, 18(22), 19-hexaen-15, 17, 17-trione (enantiomer 1) (compound 5) and 7, 7-dimethyl-11- (3- { [1- (trifluoromethyl) cyclopropyl]Methoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.1(5, 8).0(9, 14)]Tricosane-1 (21), 9(14), 10, 12, 18(22), 19-hexaene-15, 17, 17-trione (enantiomer 2) (compound 6)

Racemic 7, 7-dimethyl-11- (3- { [1- (trifluoromethyl) cyclopropyl) -11- (10mL/min) was purified using ChiralPak AS-H (250X 10mm column, 5 μm particle size) and a 20% methanol/80% carbon dioxide mobile phase (10mL/min)]Methoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.1(5, 8).0(9, 14)]Tricosane-1 (21), 9(14), 10, 12, 18(22), 19-hexaen-15, 17, 17-trione (31mg, 0.05119mmol) for chiral SFC purification to give 7, 7-dimethyl-11- (3- { [1- (trifluoromethyl) cyclopropyl-1-isomer as the first enantiomer to be eluted ]Methoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.1(5, 8).0(9, 14)]Tricosane-1 (21), 9(14), 10, 12, 18(22), 19-hexaene-15, 17, 17-trione (enantiomer 1) (compound 5) (11.5mg, 74%); ESI-MS M/z calculated 605.2032, Experimental 606.2(M +1)⁺(ii) a Retention time: 2.02min (LC method E), and 7, 7-dimethyl-11- (3- { [1- (trifluoromethyl) cyclopropyl) as the second enantiomer to be eluted]Methoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.1(5, 8).0(9, 14)]Tricosane carbon-1 (21), 9(14), 10, 12, 18 (2)2) 19-hexaen-15, 17, 17-trione (enantiomer 2) (compound 6) (11.4 mg, 72%); ESI-MS M/z calculated 605.2032, Experimental 606.2(M +1)⁺(ii) a Retention time: 2.02min (LC method E).

Example 110: preparation of 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda⁶-thia-3, 9, 11-triazatetracyclo [18.3.1.05, 10.011, 15]Tetracosane-1 (24), 5(10), 6, 8, 20, 22-hexaen-2, 2, 4-trione (enantiomer) (compound 7) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda⁶-thia-3, 9, 11-triazatetracyclo [18.3.1.05, 10.011, 15]Tetracosane-1 (24), 5(10), 6, 8, 20, 22-hexaen-2, 2, 4-trione (enantiomer 2) (compound 8)

Step 1: 2, 2-dimethyl-5- [3- (3-sulfamoylphenoxy) propyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

In a 50mL round bottom flask was added 3-hydroxybenzenesulfonamide (510mg, 2.945mmol) and N, N-dimethylformamide (10.20mL), to the mixture was added potassium carbonate (1.425g, 10.31mmol) and tert-butyl 2, 2-dimethyl-5- (3-methylsulfonyloxypropyl) pyrrolidine-1-carboxylate (1.017g, 3.033 mmol) at room temperature, and stirred at room temperature for 3h, then heated to 50 ℃ overnight, cooled to room temperature and poured into water (100mL), and extracted with ethyl acetate (2 × 100mL), the organic layers were combined, washed with water (2 × 100mL), dried (sodium sulfate), filtered and concentrated the brown residue was purified by silica gel chromatography using a gradient of 100% hexane to 100% ethyl acetate to give 2, 2-dimethyl-5- [3- (3-sulfamoylphenoxy) propyl as a light orange oil.]Pyrrolidine-1-carboxylic acid tert-butyl ester (770mg, 63%).¹H NMR (400MHz, two methanol)Sulfoxide-d ₆) 7.46(t, J ═ 8.0Hz, 1H), 7.39-7.33(M, 2H), 7.31(s, 2H), 7.13(d, J ═ 7.8Hz, 1H), 4.02(t, J ═ 6.0Hz, 2H), 3.85-3.67(M, 1H), 1.88(dd, J ═ 11.8, 6.6Hz, 2H), 1.79-1.61 (M, 4H), 1.51(dd, J ═ 37.7, 5.8Hz, 2H), 1.38(s, 12H), 1.24(s, 3H), ESI-MS M/z calculated value 412.2032, experimental value 413.2(M +1)⁺(ii) a Retention time: 1.81min (LC method E).

Step 2: 5- [3- [3- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] phenoxy ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

A100 mL flask was charged with 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] under nitrogen]Ethoxy radical]Pyrazol-1-yl]]Pyridine-3-carboxylic acid (650mg, 1.730mmol) and carbonyldiimidazole (345mg, 2.128 mmol). N, N-dimethylformamide (5.850mL) was added and the mixture was stirred at 40 ℃ under nitrogen for 1 h. In a separate 100mL flask, 2-dimethyl-5- [3- (3-sulfamoylphenoxy) propyl group was placed under nitrogen]Pyrrolidine-1-carboxylic acid tert-butyl ester (750mg, 1.818mmol) was dissolved in anhydrous N, N-dimethylformamide (5.850 mL). NaH (77.0mg, 1.925mmol) (60% oily suspension) was added in portions and the mixture was stirred under nitrogen until gas evolution ceased. The vial was capped and stirred at room temperature for 45 min. The two mixtures were combined and stirred at room temperature for 20h heated to 55 ℃ for an additional 4h, water and ice were added, followed by dropwise addition of concentrated hydrochloric acid until a white precipitate remained, then the mixture was washed with ethyl acetate, and the combined organic layers were washed with brine, followed by 1: 1 saturated aqueous solution of sodium bicarbonate/1N sodium hydroxide (3 ×), dried over sodium sulfate, filtered under vacuum and concentrated. The residue was then dissolved in 10mL of dichloromethane and purified by silica gel chromatography using a gentle gradient of 100% hexane to 65% ethyl acetate/hexane to give 5- [3- [3- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] propyl ] as a white solid ]Ethoxy radical]Pyrazole-1-Base of]Pyridine-3-carbonyl]Sulfamoyl radical]Phenoxy radical]Propyl-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (450mg, 34%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)1H NMR (400MHz, dimethyl sulfoxide) 8.39(d, J ═ 2.9Hz, 1H), 8.11(d, J ═ 8.3Hz, 1H), 7.68(d, J ═ 8.4Hz, 1H), 7.62-7.51(M, 2H), 7.46(d, J ═ 1.9Hz, 1H), 7.30(d, J ═ 6.9Hz, 1H), 6.18(d, J ═ 2.9Hz, 1H), 4.48-4.25 (M, 2H), 4.06(s, 2H), 3.74(s, 1H), 2.08(dd, J ═ 9.0, 5.1Hz, 2H), 1.88(s, 2H), 1.71 (ESI, J ═ 25.9, 15.0, 4H), 1.55 (J ═ 9.0, 5.1Hz, 2H), 7.71 (dd, 15.0, 7.7.7H), 7.7.7H, 7 (dd, 7.7H, 7.7H, 7H), 5H, 7H, 13 (dd, 15, 7H), 5H, 7H, 13 (dd, 15H, 7H, 2H), 5H, 2H), 5H, 15, 7H, 15H⁺(ii) a Retention time: 2.11min (LC method G).

And step 3: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda⁶-thia-3, 9, 11-triazatetracyclo [18.3.1.05, 10.011, 15]Tetracos-1 (24), 5(10), 6, 8, 20, 22-hexaen-2, 2, 4-trione

5- [3- [3- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] dissolved in dichloromethane (2.225mL) was combined in a 50mL round bottom flask ]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Phenoxy radical]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (445mg, 0.5777mmol), followed by addition of hydrochloric acid (4M in dioxane) (1.589mL, 4M, 6.355mmol), and stirring the mixture for 2 h. Subsequently, the material was concentrated to dryness under reduced pressure to give a material dissolved in dimethyl sulfoxide (9mL), followed by addition of excess potassium carbonate (1.0g, 7.236 mmol). The vial was capped and heated to 150 ℃ on a hot plate for 20 h. Cesium fluoride (131.6mg, 31.98 μ L, 0.8666mmol) was added and the reaction was heated to 170 ℃ for an additional 4h₁₈Column (40-70 acetonitrile-water +5mM trifluoroacetic acid) to give 12, 12-dimethyl as an off-white solid-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda⁶-thia-3, 9, 11-triazatetracyclo [18.3.1.05, 10.011, 15]Tetracosan-1 (24), 5(10), 6, 8, 20, 22-hexaen-2, 2, 4-trione (15.3mg, 4%). ESI-MS M/z calculated 633.22327, Experimental 634.2(M +1)⁺(ii) a Retention time: 1.83min (LC method E).

And 4, step 4: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester ]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda⁶-thia-3, 9, 11-triazatetracyclo [18.3.1.05, 10.011, 15]Tetracosane-1 (24), 5(10), 6, 8, 20, 22-hexaen-2, 2, 4-trione (enantiomer 1) (compound 7) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda⁶-thia-3, 9, 11-triazatetracyclo [18.3.1.05, 10.011, 15]Tetracosane-1 (24), 5(10), 6, 8, 20, 22-hexaen-2, 2, 4-trione (enantiomer 2) (compound 8)

Racemic 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] C.sub.1-methyl using ChiralPak AS-H (250X 10mm column, 5 μm particle size) and 18% methanol/82% carbon dioxide mobile phase (10mL/min)]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda⁶-thia-3, 9, 11-triazatetracyclo [18.3.1.05, 10.011, 15]Chiral SFC purification of tetracosane-1 (24), 5(10), 6, 8, 20, 22-hexaen-2, 2, 4-trione (15.3mg, 0.02414mmol) to give 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] ketone as the first enantiomer to be eluted as an off-white solid]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda⁶-thia-3, 9, 11-triazatetracyclo [18.3.1.05, 10.011, 15 ]Tetracosane-1 (24), 5(10), 6, 8, 20, 22-hexaen-2, 2, 4-trione (enantiomer 1) (compound 7) (3.4mg, 44%), calculated ESI-MS M/z 633.22327, experimental 634.2(M +1)⁺(ii) a Retention time: 1.84min (LC method E), and as the second enantiomer to be eluted as an off-white solid12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda⁶-thia-3, 9, 11-triazatetracyclo [18.3.1.05, 10.011, 15]Tetracosane-1 (24), 5(10), 6, 8, 20, 22-hexaen-2, 2, 4-trione (enantiomer 2) (compound 8) (3.4mg, 44%), ESI-MS M/z calculated 633.22327, experimental 634.2(M +1)⁺(ii) a Retention time: 1.84min (LC method E).

Example 111: preparation of 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracosane-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (compound 16)

To a vial was added potassium carbonate (495mg, 3.582mmol), tert-butyl 5- (3-aminopropyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (304mg, 1.19mmol), 6-fluoropyridine-2-sulfonamide (208.9mg, 1.186 mmol) and dimethyl sulfoxide (3 mL). The reaction was stirred at 80 ℃ overnight. The reaction was filtered and purified by HPLC (1% to 99% acetonitrile/water + 0.1% hydrochloric acid modifier gradient) to give 2, 2-dimethyl-5- [3- [ (6-sulfamoyl-2-pyridyl) amino as a white foam ]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (224.7mg, 46%). ESI-MS M/z calculated 412.21442, Experimental value 413.8(M +1)⁺(ii) a Retention time: 0.94min (LC method B).

Step 2: 5- [3- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

Adding 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] to a round bottom flask]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (204mg, 0.5429mmol), carbonyldiimidazole (93mg, 0.5735mmol) and tetrahydrofuran (3 mL). The reaction was purged with nitrogen and placed in a preheated 45 ℃ oil bath for 90min. 2, 2-dimethyl-5- [3- [ (6-sulfamoyl-2-pyridyl) amino was added]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (224mg, 0.5430 mmol) followed by the addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (250 μ L, 1.672mmol) and the reaction was stirred at room temperature overnight. The reaction was filtered and purified by HPLC (30% -99% acetonitrile/water + 0.1% hydrochloric acid modifier gradient) to give 5- [3- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl ]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (196.5mg, 47%). ESI-MS M/z calculated 769.2636, experimental 770.5 (M +1)⁺(ii) a Retention time: 1.98min (LC method B).

And step 3: 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-2-yl) propylamino ] -2-pyridinyl ] sulfonyl ] -6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide

Adding 5- [3- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] to a round bottom flask]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (195mg, 0.2532mmol) and dichloromethane (5 mL). Hydrochloric acid (1.3mL 4M in dioxane, 5.200mmol) was added dropwise and the reaction stirred at room temperature for 1h the reaction was evaporated to dryness, the reaction was diluted to pH 10 with 3M potassium carbonate and extracted three times with ethyl acetate the combined organic layers were dried over sodium sulfate, filtered and evaporated to give 2-chloro-N- [ [6-[3- (5, 5-dimethylpyrrolidin-2-yl) propylamino group]-2-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (169mg, 100%). ESI-MS M/z calculated 669.2112, Experimental 670.5(M +1) ⁺(ii) a Retention time: 0.78min (LC method B).

And 4, step 4: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracosane-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (compound 16)

To a vial were added potassium carbonate (175mg, 1.266mmol), cesium fluoride (58mg, 0.3818mmol) and 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-2-yl) propylamino]-2-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (169mg, 0.2522 mmol) in dimethylsulfoxide (3.0mL), the reaction was heated in a sealed tube at 150 ℃ overnight, quenched with brine and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated the crude reaction mixture was purified by silica gel chromatography (0% -50% ethyl acetate/dichloromethane gradient) to give 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracosan-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (compound 16) (93mg, 58%). ¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.75(s， 1H)，8.23(d，J＝2.7Hz，1H)，8.01(d，J＝8.2Hz，1H)，7.58(t，J＝7.8Hz，1H)，7.29(s， 1H)，7.03(d，J＝7.2Hz，2H)，6.63(d，J＝8.4Hz，1H)，6.13(d，J＝2.7Hz，1H)，4.32 (t，J＝7.1Hz，2H)，3.72(s，2H)，3.10(s，1H)，2.08(t，J＝7.0Hz，2H)，1.86(s，2H)， 1.73(s，2H)，1.51(s，4H)，1.35(s，3H)，1.24(s，2H)，1.02-0.93(m，3H)，090-0.85 (M, 2H). ESI-MS M/z calculated 633.2345, Experimental 634.2(M +1)⁺(ii) a Retention time: 1.85min (LC method B).

Example 112: preparation of 20, 20, 22-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (compound 18) and 12, 20, 20-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (Compound 19)

Step 1: 2-chloro-N- [ (5-methyl-1H-pyrazol-4-yl) sulfonyl ] -6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide

Adding 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] to a vial]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (100mg, 0.2661mmol), carbonyldiimidazole (48mg, 0.30mmol) and tetrahydrofuran (1 mL). The reaction was stirred at 45 ℃ for 1 h.5-methyl-1H-pyrazole-4-sulfonamide (43mg, 0.2668mmol) and 1, 8-diazabicyclo [5.4.0 ] were added ]Undec-7-ene (125 μ L, 0.836mmol) and the reaction stirred at 45 ℃ overnight the crude reaction was filtered and purified by HPLC (10% -99% acetonitrile/water + 0.1% hydrochloric acid modifier gradient) to give 2-chloro-N- [ (5-methyl-1H-pyrazol-4-yl) sulfonyl]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (80.0mg, 58%). ESI-MS M/z calculated 518.0751, Experimental 519.1(M +1)⁺(ii) a Retention time: 1.7min (LC method B).

Step 2: 4- [3- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -3-methyl-pyrazol-1-yl ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 4- [3- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -5-methyl-pyrazol-1-yl ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (mixture of regioisomers)

To a solution containing 2-chloro-N- [ (5-methyl-1H-pyrazol-4-yl) sulfonyl group]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (80mg, 0.1542mmol) in a round-bottomed flask was added N, N-dimethylformamide (2mL), potassium carbonate (65mg, 0.47mmol) and N, N-dimethylformamide (2mL) containing tert-butyl 2, 2-dimethyl-4- (3-methylsulfonyloxypropyl) pyrrolidine-1-carboxylate (68mg, 0.20 mmol). The reaction was heated at 60 ℃ and stirred for 4 days. The reaction was filtered and purified by HPLC (30% -99% acetonitrile/water + 0.1% hydrochloric acid modifier gradient) to give 4- [3- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] as a white foam ]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-3-methyl-pyrazol-1-yl]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 4- [3- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-5-methyl-pyrazol-1-yl]Propyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (mixture of regioisomers) (49.9mg, 43%). ESI-MS calc/z 757.2636, experimental 758.4(M +1)⁺(ii) a Retention time: 1.82min (LC method G).

And step 3: 2-chloro-N- [1- [3- (5, 5-dimethylpyrrolidin-3-yl) propyl ] -3-methyl-pyrazol-4-yl ] sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide and 2-chloro-N- [1- [3- (5, 5-dimethylpyrrolidin-3-yl) propyl ] -5-methyl-pyrazol-4-yl ] sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide (mixture of regioisomers).

Adding 4- [3- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] to a round bottom flask]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-3-methyl-pyrazol-1-yl]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 4- [3- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] methyl ester ]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-5-methyl-pyrazol-1-yl]Propyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (mixture of regioisomers) (49.9mg, 0.0658mmol), dioxane (1mL) and hydrochloric acid (165 μ L4M in dioxane, 0.660 mmol). The reaction was heated at 35 ℃ overnight, quenched with saturated sodium bicarbonate, and extracted with ethyl acetate the organic layer was dried over sodium sulfate, filtered, and evaporated to afford 2-chloro-N- [1- [3- (5, 5-dimethylpyrrolidin-3-yl) propyl ] as a white solid]-3-methyl-pyrazol-4-yl]Sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide and 2-chloro-N- [1- [3- (5, 5-dimethylpyrrolidin-3-yl) propyl ] amide]-5-methyl-pyrazol-4-yl]Sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (mixture of regioisomers) (42mg, 97%). ESI-MS M/z calculated 657.2112, Experimental 658.4(M +1)⁺(ii) a Retention time: 0.74min (LC method B).

And 4, step 4: 20, 20, 22-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7 ]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (compound 18) and 12, 20, 20-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (Compound 19)

To the solution containing 2-chloro-N- [1- [3- (5, 5-dimethylpyrrolidin-3-yl) propyl group]-3-methyl-pyrazol-4-yl]Sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide and 2-chloro-N- [1- [3- (5, 5-dimethylpyrrolidin-3-yl) propyl ] amide]-5-methyl-pyrazol-4-yl]Sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (mixture of regioisomers) (42mg, 0.06382mmol) in a round-bottomed flask was added potassium carbonate (44mg, 0.32mmol), cesium fluoride (50mg, 0.33 mmol), dimethyl sulfoxide (2mL) and four

Molecular sieves the reaction was heated at 150 ℃ overnight. The reaction was cooled to room temperature, filtered, and purified by HPLC (10% -99% acetonitrile/water + 0.1% hydrochloric acid modifier gradient) to give 20, 20, 22-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as an orange solid as the first isomer to be eluted ]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (compound 18) (2.8mg, 7%);¹h NMR (400MHz, dimethylsulfoxide-d)₆)12.39(s, 1H), 8.18(d, J ═ 2.8Hz, 1H), 7.86(s, 1H), 7.77(d, J ═ 8.3Hz, 1H), 6.90(d, J ═ 8.2Hz, 1H), 6.09(d, J ═ 2.7 Hz, 1H), 4.43-4.34(M, 1H), 4.30(t, J ═ 7.0Hz, 2H), 4.08-3.96(M, 1H), 2.06(q, J ═ 7.4Hz, 6H), 1.95-1.69(M, 4H), 1.55(s, 3H), 1.47(s, 3H), 1.40-1.08(M, 4H), 0.96(td, J ═ 4.9, 4.4, 3.90, 0.84H), experiment calculated values of M, 8585H, M, 2H, M, 2, M⁺(ii) a Retention time: 1.48min (LC method B) and 12, 20, 20-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as an orange solid of the second isomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (compound 19) (3.7mg, 9%);¹h NMR (400MHz, dimethylsulfoxide-d)₆)12.18(s, 1H), 8.41(s, 1H), 8.18(d, J ═ 2.8Hz, 1H), 7.75(d, J ═ 8.2Hz, 1H), 6.89(d, J ═ 8.2Hz, 1H), 6.10(d, J ═ 2.8Hz, 1H), 4.31(t, J ═ 7.0Hz, 2H), 4.22(dt, J ═ 13.6, 3.8Hz, 1H), 3.97(t, J ═ 12.4Hz, 1H), 2.40(s, 3H), 2.20(s, 1H), 2.07(t, J ═ 7.1Hz, 4H), 2.02-1.68(M, 4H), 1.51(d, J ═ 13.0, 6H), 1.38(t, J ═ 3.3, 1H), 3.5 (t, J ═ 3.5, 2.5, 2.3.5H), 2.3.3.3.3H, 2.5 (M ═ 3.3.2.2H), 2.2.3.3.2.2H), 2.2.2.2.2 ⁺(ii) a Retention time: 1.54min (LC method B).

Example 113: preparation of 7, 7-dimethyl-11- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosane-1 (21), 9, 11, 13, 18(22), 19-hexaene-15, 17, 17-trione (compound 20)

Step 1: 4- [2- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] ethyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

Adding 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] to a vial]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (615mg, 1.64mmol), carbonyldiimidazole (279mg, 1.72mmol) and tetrahydrofuran (3 mL). The reaction was stirred at 45 ℃ for 2h, 2-dimethyl-4- [2- [ (6-sulfamoyl-2-pyridyl) amino ] was added]Ethyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (654mg, 1.641mmol) and subsequent addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (750 μ L, 5.02mmol) and the reaction was stirred at 45 ℃ overnight. The reaction was quenched with 1N citric acid and extracted with ethyl acetate the organic layer was dried over sodium sulfate, filtered and evaporated. By silica gel chromatography (10% -100% ethyl acetate/hexanes gradient) the crude reaction mixture was purified to give 4- [2- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Ethyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (830mg, 67%). ESI-MS M/z calculated 755.248, Experimental 756.5(M +1)⁺(ii) a Retention time: 1.8min (LC method G).

Step 2: 2-chloro-N- [ [6- [2- (5, 5-dimethylpyrrolidin-3-yl) ethylamino ] -2-pyridinyl ] sulfonyl ] -6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide

To a solution containing 4- [2- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] carbonyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Ethyl radical]To a round bottom flask of-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (830mg, 1.098mmol) were added dichloromethane (2mL) and hydrochloric acid (2.75mL, 4M in dioxane, 11.00 mmol). After 40min, the reaction was quenched with saturated sodium bicarbonate and extracted twice with ethyl acetate the combined organic layers were dried over sodium sulfate, filtered and evaporated to afford 2-chloro-N- [ [6- [2- (5, 5-dimethylpyrrolidin-3-yl) ethylamino ] as a white solid ]-2-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (715mg, 99%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)8.35(d，J＝2.8Hz，1H)，8.11(d，J＝8.3Hz，1H)，7.62(d，J＝8.2Hz， 1H)，7.44(dd，J＝8.3，7.3Hz，1H)，6.98(dd，J＝7.2，0.8Hz，1H)，6.84(t，J＝5.8Hz， 1H)，6.47(dd，J＝8.3，0.8Hz，1H)，6.12(d，J＝2.8Hz，1H)，4.33(t，J＝7.0Hz，2H)， 3.81-3.69(m，1H)，3.17(dq，J＝12.3，5.8Hz，1H)，3.09-2.97(m，1H)，2.39(p，J＝ 8.0Hz，1H)，2.08(t，J＝7.1Hz，2H)，1.95(dd，J＝12.8，7.7Hz，1H)，1.62(dp，J＝ 19.9，6.4Hz，2H)，1.35(dd，J＝12.8，10.2Hz，1H)，1.26(d，J＝32.0Hz，6H)，101-0.84 (M, 4H). ESI-MS M/z calculated 655.19556, Experimental 656.6(M +1)⁺(ii) a Retention time: 0.78min (LC method B).

And step 3: 7, 7-dimethyl-11- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosane-1 (21), 9, 11, 13, 18(22), 19-hexaene-15, 17, 17-trione (compound 20)

To a vial were added potassium carbonate (263mg, 1.90mmol), cesium fluoride (133mg, 0.876mmol), four

Molecular sieves, 2-chloro-N- [ [6- [2- (5, 5-dimethylpyrrolidin-3-yl) ethylamino]-2-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (250mg, 0.381 mmol) and dimethylsulfoxide (7 mL). The reaction was capped and placed in a preheated oil bath at 155 ℃ overnight. The reaction was diluted with ethyl acetate and quenched with 1N citric acid, then with brine. The crude reaction mixture was purified by silica gel chromatography (0% -100% ethyl acetate/hexane gradient) to provide 7, 7-dimethyl-11- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methane ]Ethoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosane-1 (21), 9, 11, 13, 18(22), 19-hexaen-15, 17, 17-trione (Compound 20) (101mg, 43%). ESI-MS M/z Calculation 619.2189, Experimental 620.2(M +1)⁺(ii) a Retention time: 2.07min (LC method B).

Example 114: preparation of 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 22-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione(hydrochloride salt) (Compound 23)

Step 1: 2, 2-dimethyl-4- [3- [ (2-sulfamoyl-4-pyridyl) amino ] propyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 2, 2-dimethyl-4- (3-methylsulfonyloxypropyl) pyrrolidine-1-carboxylate (300mg, 0.894mmol) in N, N-dimethylformamide (5mL) were added 4-aminopyridine-2-sulfonamide (310mg, 1.79mmol) and cesium carbonate (900mg, 2.76 mmol). The reaction mixture was stirred at 70 ℃ for 4 h. The reaction mixture was cooled to room temperature and poured into water (100mL) and extracted with ethyl acetate (2 × 100mL), the organic layers were combined, washed with brine, dried (sodium sulfate), filtered and concentrated to give 2, 2-dimethyl-4- [3- [ (2-sulfamoyl-4-pyridyl) amino ]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (369mg, quantitative) was used directly in the next step.¹H NMR (400MHz, dimethylsulfoxide-d)₆)8.32(brs, 2H), 8.12(dd, J ═ 6.6, 1.6Hz, 1H), 7.24(dd, J ═ 6.3, 2.4Hz, 1H), 6.87(dt, J ═ 6.7, 2.0Hz, 1H), 3.50 (q, J ═ 9.0Hz, 2H), 3.40-3.28(M, 1H), 2.96(p, J ═ 7.0, 6.4Hz, 2H), 2.83-2.68(M, 1H), 2.07-1.96(M, 1H), 1.89-1.74(M, 2H), 1.45-1.26(M, 14H), 1.23(s, 3H), ESI-MS M/z, calculated value 412.21442, experimental value 413.5(M +1)⁺(ii) a Retention time: 0.52min (LC method A).

Step 2: 4- [3- [ [2- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -4-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]A solution of pyridine-3-carboxylic acid (300mg, 0.798mmol) and carbonyldiimidazole (130mg, 0.802mmol) in tetrahydrofuran (5mL) was stirred for 45 min. Subsequently, 2-dimethyl-4- [3- [ (2-sulfamoyl-4-pyridyl) amino group was added]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (330mg, 0.800mmol) and 1, 8-diazabicyclo [5.4.0 ]Undec-7-ene (150 μ L, 1.00 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated to give an oily material which was purified by reverse phase HPLC-MS using Luna C sold by Phenomenex₁₈(2) Column (75 × 30mM, 5 μm particle size) (pn: 00C-4252-U0-AX) and dual gradient run of 15.0min 1% -99% mobile phase B (mobile phase a ═ water (5mM hydrochloric acid), mobile phase B ═ acetonitrile, flow rate ═ 50 mL/min, injection volume ═ 950 μ L and column temperature ═ 25 ℃) purification gave the desired product 4- [3- [ [2- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] as an off-white sticky mass]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-4-pyridinyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (23mg, 4%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)8.40(d, J ═ 2.8Hz, 1H), 8.15(d, J ═ 5.6Hz, 1H), 7.96(d, J ═ 8.3Hz, 1H), 7.66(d, J ═ 8.3Hz, 1H), 7.00(d, J ═ 2.2Hz, 1H), 6.80 (s, 2H), 6.69(dd, J ═ 5.7, 2.2Hz, 1H), 6.18(d, J ═ 2.8Hz, 1H), 4.34(t, J ═ 7.1Hz, 2H), 3.81-3.71(M, 1H), 3.54(q, J ═ 8.3Hz, 1H), 2.77(q, J ═ 10.0Hz, 1H), 2.18-2.02 (M, 4.90H), 1.54 (q, J ═ 8.3Hz, 1H), 2.77(q, J ═ 10.0Hz, 1H), 1H, 2.18-2.02 (M, 1H), 1.90 (M, 1.84, 1.3, 1H), 5(M, 1H), 1H, 3M, 3, 1H, 3.7, 1H), 5(M, 1H), 5, 1H, 3M, 3, 1H), 2.⁺(ii) a Retention time: 0.87min (LC method A).

And step 3: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 22-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione(hydrochloride salt) (Compound 23)

Reacting 4- [3- [ [2- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] group]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-4-pyridinyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (20mg, 0.026mmol) was dissolved in dioxane (1.0mL) and to this mixture hydrochloric acid (4M in dioxane) (250 μ L, 4M, 1.0mmol) was added and the resulting mixture was stirred at room temperature for 3h the mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate and then 2M aqueous sodium carbonate (5mL) was added, pH about 10 the organic layer was extracted with ethyl acetate (2 × 10mL), washed with brine, then dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure to give the material which was combined in a vial with potassium carbonate (20mg, 0.14mmol), cesium fluoride (10mg, 0.066mmol) and dimethyl sulfoxide (2.0 mL). The vial was purged with nitrogen, capped, heated to 150 ℃ and stirred for 16h cooled to room temperature and the reaction mixture was filtered through Whatman filter disc (puradisc 25 TF) and by reverse phase HPLC-MS method using Luna C sold by Phenomenex ₁₈(2) The filtrate was purified by dual gradient run of a column (75 × 30mM, 5 μm particle size) (pn: 00C-4252-U0-AX) and 50% -99% mobile phase B over 15.0min (mobile phase a ═ water (5mM hydrochloric acid), mobile phase B ═ acetonitrile ═ 50mL/min, injection volume of 950 μ L and column temperature of 25 ℃) to give 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl) as a white solid]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 22-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (hydrochloride) (compound 23) (1.6mg, 9%). ESI-MS M/z calculated 633.2345, Experimental 634.6(M +1)⁺(ii) a Retention time: 2.15min (LC method B).

Example 115: preparation of 6, 6-dimethyl-10- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -16 lambda⁶-thia-2, 7, 9, 15, 21-pentaazatetracyclo [15.3.1.14, 7.08, 13]Twenty-fourTwo carbon-1 (20), 8, 10, 12, 17(21), 18-hexaene-14, 16, 16-trione (compound 17)

Step 1: 4- (hydroxymethyl) -2, 2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester

(1-benzyl-5, 5-dimethylpyrrolidin-3-yl) methanol (1g, 4.56mmol) was dissolved in EtOH (40 mL) and 20% Pd (OH) was added ₂Carbon (400mg) and the reaction mixture was stirred at 20 ℃ under an atmosphere of hydrogen for 24 h. The catalyst was filtered off over celite, the filter cake was washed with ethyl acetate and the filtrate was concentrated. The crude intermediate was dissolved in tetrahydrofuran/water (50mL/50mL) and potassium carbonate (3.1g, 22.8 mmol) was added at 0 deg.C followed by Boc₂O (1.22g, 4.56 mmol). The reaction mixture was warmed to 20 ℃ over 16h, then poured into water and extracted with ethyl acetate (3X 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. After purification on silica gel (30% ethyl acetate/heptane eluent), pure tert-butyl 4- (hydroxymethyl) -2, 2-dimethylpyrrolidine-1-carboxylate (1.04g, quantitative) was obtained as a colorless oil.¹H NMR(300MHz， CDCl₃)：d 3.6(m，4H)；3.1(m，1H)；2.4(m，1H)；1.9(m，1H)；1.4(m，15H)。

Step 2: 4- (aminomethyl) -2, 2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester

MsCl (0.57mL, 7.3mmol) was added slowly to a solution of tert-butyl 4- (hydroxymethyl) -2, 2-dimethylpyrrolidine-1-carboxylate (1.4g, 6.1mmol) and DIPEA (1.6mL, 9.15mmol) in dichloromethane (30mL) at 0 deg.C the reaction mixture was stirred for 1h, water was added, the layers were separated and washed with waterThe aqueous layer was extracted with dichloromethane (2 × 10mL), the combined organic layers were dried over sodium sulfate, filtered and concentrated the crude methanesulfonate was dissolved in N, N-dimethylformamide (20mL), NaN3(600mg, 9.15mmol) was added and the reaction mixture was stirred in a closed vessel at 100 ℃ for 16h. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude azide was dissolved in tetrahydrofuran/water (18/2mL), PPh3(2.4g, 9.15mmol) was added and the reaction mixture was stirred at 50 ℃ for 3h the reaction mixture was cooled, carefully acidified to pH3 with 4N aqueous hydrochloric acid and washed rapidly with ethyl acetate (2 × 20mL), the aqueous layer was basified to pH 10 and extracted with ethyl acetate (3 × 10mL), the combined organic layers were dried over sodium sulfate, filtered and concentrated to give tert-butyl 4- (aminomethyl) -2, 2-dimethylpyrrolidine-1-carboxylate (600mg, 43%) as a yellow oil after purification on silica gel (5% methanol/dichloromethane eluent). ¹H NMR(300MHz，CDCl₃)：d 3.7(m，1H)；3.0(m，1H)； 2.7(m，2H)；2.2(m，1H)；1.9(m，1H)；1.4(m，15H).

And step 3: 2, 2-dimethyl-4- [ [ (6-sulfamoyl-2-pyridyl) amino ] methyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

In a 20mL vial 6-fluoropyridine-2-sulfonamide (340mg, 1.9mmol) was combined in dimethylsulfoxide (4.0mL), followed by potassium carbonate (1.3g, 9.4mmol) and tert-butyl 4- (aminomethyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (460mg, 2.0 mmol). The vial was capped and heated to 100 ℃ on a hot plate for 16 h. The reaction mixture was cooled to room temperature, then filtered, and diluted with ethyl acetate and washed with 1M citric acid solution followed by brine the organics were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexane to 80% ethyl acetate/hexane to give 2, 2-dimethyl-4- [ [ (6-sulfamoyl-2-pyridine) as a white solidRadical) amino]Methyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (222mg, 30%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)7.53(dd, J ═ 8.4, 7.3 Hz, 1H), 7.10(s, 2H), 7.06(d, J ═ 5.5Hz, 1H), 6.97(d, J ═ 6.9Hz, 1H), 6.64(d, J ═ 8.1Hz, 1H), 3.65-3.54(m, 1H), 3.17(d, J ═ 5.2Hz, 2H), 2.95(t, J ═ 10.1Hz, 1H), 2.47-2.35(m, 1H), 2.00-1.86(m, 1H), 1.55(dt, J ═ 32.7, 12.1Hz, 1H), 1.42-1.36 (m, 12H), 1.25(s, 3H). ESI-MS M/z calculated 384.18314, Experimental 385.2(M +1) ⁺(ii) a Retention time: 1.46min (LC method E).

And 4, step 4: 4- [ [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] methyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (202mg, 0.538mmol) and carbonyldiimidazole (87.5mg, 0.540mmol) were combined in tetrahydrofuran (3.0mL) and stirred at 45 ℃ for 2h, then 2, 2-dimethyl-4- [ [ (6-sulfamoyl-2-pyridyl) amino ] was added]Methyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (207mg, 0.538mmol) was added followed by 1, 8-diazabicyclo [5.4.0]Undec-7-ene (175 μ L, 1.17mmol) and the reaction heated at 50 ℃ for 16h, the reaction was diluted with ethyl acetate and washed with 1M citric acid solution followed by brine the organics were separated, dried over sodium sulfate, filtered and evaporated followed by silica gel chromatography using a gradient of 100% hexane to 70% ethyl acetate/hexane to give 4- [ [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] as a pale yellow solid]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl ]Amino group]Methyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (234mg, 59%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.79(s，1H)，8.40(m， 1H)，8.09(d，J＝8.4Hz，1H)，7.70(t，J＝7.0Hz，1H)，7.63(m，1H)，7.28(s，1H)，7.19 (d，J＝7.2Hz, 1H), 6.77(d, J ═ 8.6Hz, 1H), 6.19(dd, J ═ 4.4, 2.9Hz, 1H), 4.34(t, J ═ 7.1Hz, 2H), 3.55(m, 1H), 3.26(m, 2H), 2.91(t, J ═ 10.4Hz, 1H), 2.41(m, 1H), 2.09 (t, J ═ 7.1Hz, 3H), 1.86(m, 1H), 1.50(m, 1H), 1.35(t, J ═ 13.2Hz, 12H), 1.18(s, 3H), 0.95(m, 2H), 0.89(s, 2H). ESI-MS M/z calculated 741.2323, Experimental 742.2 (M +1)⁺(ii) a Retention time: 2.25min (LC method E).

And 5: 6, 6-dimethyl-10- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -16 lambda⁶-thia-2, 7, 9, 15, 21-pentaazatetracyclo [15.3.1.14, 7.08, 13]Docosal-1 (20), 8, 10, 12, 17(21), 18-hexaen-14, 16, 16-trione (Compound 17)

4- [ [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Methyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (234mg, 0.315 mmol) was dissolved in dichloromethane (5.0mL) and to this mixture hydrochloric acid (3.0mL, 4M in dioxane, 12.0mmol) was added and stirred at room temperature for 2h the mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate and then 2M aqueous sodium carbonate (2mL) was added, pH about 10. the organic layer was extracted with ethyl acetate (2 × 5mL), washed with brine, then dried over sodium sulfate, filtered, and evaporated to dryness under reduced pressure. This material was mixed with potassium carbonate (220mg, 1.59mmol), cesium fluoride (72.0mg, 0.474mmol),

Molecular sieves and dimethylsulfoxide (7.0mL) were combined in a vial, purged with nitrogen, capped, heated to 155 ℃, and stirred for 16 h. Cooled to room temperature and the reaction was diluted with ethyl acetate and washed with 1M citric acid solution followed by brine the organics were separated, dried over sodium sulfate, filtered and evaporated, followed by chromatography on silica gel using 100% hexane to 80%Gradient purification of ethyl acetate/hexane afforded 6, 6-dimethyl-10- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Ethoxy } -1H-pyrazol-1-yl) -16 lambda⁶-thia-2, 7, 9, 15, 21-pentaazatetracyclo [15.3.1.14, 7.08, 13]Docosal-1 (20), 8, 10, 12, 17(21), 18-hexaen-14, 16, 16-trione (compound 17) (111mg, 57%).¹H NMR (400MHz, dimethylsulfoxide-d)₆) 12.52(s, 1H), 8.19(d, J ═ 2.7Hz, 1H), 7.67-7.50(m, 2H), 7.47(d, J ═ 8.1Hz, 1H), 7.16(d, J ═ 7.2Hz, 1H), 6.82(d, J ═ 8.1Hz, 1H), 6.73(d, J ═ 8.5Hz, 1H), 6.09(d, J ═ 2.7Hz, 1H), 4.52(t, J ═ 9.8Hz, 1H), 4.30(t, J ═ 7.0Hz, 2H), 3.54-3.42(m, 1H), 3.27-3.16(m, 1H), 3.02(t, J ═ 8.7, 1H), 2.32(dt, 12.5, 3.42(m, 1H), 3.27-3.16(m, 1H), 3.02(t, J ═ 8.7, 1H), 8.32 (dt, 8, 8.5H), 8, 8.5H, 1H), 8, 1H, 8, 1H, 8, 5 (d, 1H), 2H) in that respect ESI-MS M/z calculated 605.2032, Experimental 606.4(M +1) ⁺(ii) a Retention time: 2.02min (LC method E).

Example 116: preparation of 6, 6-dimethyl-10- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -16 lambda⁶-thia-2, 7, 9, 15, 21-pentaazatetracyclo [15.3.1.14, 7.08, 13]Docosac-1 (20), 8, 10, 12, 17(21), 18-hexaen-14, 16, 16-trione (enantiomer 1) (compound 24) and 6, 6-dimethyl-10- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -16 lambda⁶-thia-2, 7, 9, 15, 21-pentaazatetracyclo [15.3.1.14, 7.08, 13]Docosal-1 (20), 8, 10, 12, 17(21), 18-hexaen-14, 16, 16-trione (enantiomer 2) (compound 25)

Step 1: 6, 6-dimethyl-10- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -16 lambda⁶-thia-2, 7, 9, 15, 21-pentaazatetracyclo [15.3.1.14, 7.08, 13]Docosate-1 (20), 8, 10, 12, 17(21),18-hexaen-14, 16, 16-trione (enantiomer 1) (compound 24) and 6, 6-dimethyl-10- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -16 lambda⁶-thia-2, 7, 9, 15, 21-pentaazatetracyclo [15.3.1.14, 7.08, 13]Docosal-1 (20), 8, 10, 12, 17(21), 18-hexaen-14, 16, 16-trione (enantiomer 2) (compound 25)

Racemic 6, 6-dimethyl-10- (3- {2- [1- (trifluoromethyl) cyclopropyl ] -10 using ChiralPak AS-H (250X 21.2mm column, 5 μm particle size) and a mobile phase of 15% acetonitrile: methanol (90: 10)/85% carbon dioxide (10mL/min)]Ethoxy } -1H-pyrazol-1-yl) -16 lambda⁶-thia-2, 7, 9, 15, 21-pentaazatetracyclo [15.3.1.14, 7.08, 13]Didodec-1 (20), 8, 10, 12, 17(21), 18-hexaen-14, 16, 16-trione (131mg) was subjected to chiral SFC chromatography to give 6, 6-dimethyl-10- (3- {2- [1- (trifluoromethyl) cyclopropyl-n-propyl ] 10 as the first enantiomer to be eluted as an off-white solid]Ethoxy } -1H-pyrazol-1-yl) -16 lambda⁶-thia-2, 7, 9, 15, 21-pentaazatetracyclo [15.3.1.14, 7.08, 13]Docosal-1 (20), 8, 10, 12, 17(21), 18-hexaen-14, 16, 16-trione (enantiomer 1) (compound 24) (29.04mg, 69%);¹h NMR (400MHz, dimethylsulfoxide-d)₆)12.52(s, 1H), 8.19(d, J ═ 2.7Hz, 1H), 7.61(dd, J ═ 10.5, 5.2Hz, 2H), 7.47(d, J ═ 8.1Hz, 1H), 7.16(d, J ═ 7.2Hz, 1H), 6.82(d, J ═ 8.1Hz, 1H), 6.73(d, J ═ 8.5Hz, 1H), 6.09(d, J ═ 2.7Hz, 1H), 4.51(t, J ═ 10.0Hz, 1H), 4.30(t, J ═ 7.0Hz, 2H), 3.58-3.38(m, 1H), 3.22(d, J ═ 5.6Hz, 1H), 3.95-2.95 (m, 1H, 2H), 3.58-3.38(m, 1H), 3.22(d, J ═ 5.6Hz, 1H), 1H, 3.95 (m, 1H), 3.5.5H, 7, 7.5H, 7H, 1H, 7H, 1H, 7.5H, 7H, 1H, 7H, 1H, 7H, experimental value 606.2(M +1) ⁺(ii) a Retention time: 2.03min (LC method E) and 6 as off-white solid as the second enantiomer to be eluted,6-dimethyl-10- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -16 lambda⁶-thia-2, 7, 9, 15, 21-pentaazatetracyclo [15.3.1.14, 7.08, 13]Docosal-1 (20), 8, 10, 12, 17(21), 18-hexaen-14, 16, 16-trione (enantiomer 2) (compound 25) (28.84mg, 68%);¹h NMR (400MHz, dimethylsulfoxide-d)₆)12.52(s, 1H), 8.19(d, J ═ 2.7Hz, 1H), 7.61(dd, J ═ 10.3, 5.4Hz, 2H), 7.47(d, J ═ 8.1Hz, 1H), 7.16(d, J ═ 7.2Hz, 1H), 6.82(d, J ═ 8.1Hz, 1H), 6.73(d, J ═ 8.4Hz, 1H), 6.09(d, J ═ 2.7Hz, 1H), 4.51 (t, J ═ 9.9Hz, 1H), 4.30(t, J ═ 7.0Hz, 2H), 3.58-3.41(m, 1H), 3.22 (J, J ═ 12.0, 5.7, 1H), 3.02(t, 8.0 Hz, 2H), 3.58-3.41(m, 1H), 3.22(dd, J ═ 12.0, 5.7, 1H), 3.02(t, 6.0, 7, 7.7, 7H), 6.7, 7, 1H), 7, 1H, 6.7H, 1H, 7H, 1H, 6.7H, 1H, 7H, 1H, 7H, 6.7H, 1H, 6.7H, 7H, 1H, 7H, 6.6.7H, 1H, 7H, 1H, 2H) ESI-MS calculated M/z 605.2032, Experimental 606.2 (M +1)⁺(ii) a Retention time: 2.03min (LC method E).

Example 117: preparation of 7, 7-dimethyl-11- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosano-1 (21), 9, 11, 13, 18(22), 19-hexaen-15, 17, 17-trione (enantiomer 1) (compound 26) and 7, 7-dimethyl-11- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosane-1 (21), 9, 11, 13, 18(22), 19-hexaene-15, 17, 17-trione (enantiomer 2) (compound 27)

Step 1: 7, 7-dimethyl-11- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosane-1 (21), 9, 11, 13, 18(22), 19-hexaene-15, 17, 17-trione(enantiomer 1) (Compound 26) and 7, 7-dimethyl-11- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosane-1 (21), 9, 11, 13, 18(22), 19-hexaene-15, 17, 17-trione (enantiomer 2) (compound 27)

Racemic 7, 7-dimethyl-11- (3- {2- [1- (trifluoromethyl) cyclopropyl ] -11- (3- {2- [ 2- (trifluoromethyl)) was purified using a ChiralPak AS-H (250X 21.2mm column, 5 μm particle size) and 20% methanol (no modifier)/80% carbon dioxide mobile phase (10mL/min)]Ethoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Ditridec-1 (21), 9, 11, 13, 18(22), 19-hexaen-15, 17, 17-trione (85mg, 0.1372mmol) was subjected to chiral SFC chromatography to give 7, 7-dimethyl-11- (3- {2- [1- (trifluoromethyl) cyclopropyl ] ketone as the first enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosano-1 (21), 9, 11, 13, 18(22), 19-hexaen-15, 17, 17-trione (enantiomer 1) (compound 26) (24.1mg, 28%); ESI-MS M/z calculated 619.2189, Experimental 620.2(M +1)⁺(ii) a Retention time: 2.07min (LC method B) and 7, 7-dimethyl-11- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as the second enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosano-1 (21), 9, 11, 13, 18(22), 19-hexaen-15, 17, 17-trione (enantiomer 2) (compound 27) (26mg, 31%); ESI-MS M/z calculated 619.2189, Experimental 620.2(M +1) ⁺(ii) a Retention time: 2.06min (LC method B).

Example 118: preparation of 4-chloro-20, 20-dimethyl-10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (compound A) and 4-chloro-21, 21-dimethyl-10 lambda⁶-thia-1, 3, 9, 14, 15-pentaazatetracyclo [17.2.1.02, 7.011, 15-]Docosac-2, 4, 6, 11, 13-pentaene-8, 10, 10-trione (Compound B)

Step 1: 2, 6-dichloro-N- (1H-pyrazol-3-ylsulfonyl) pyridine-3-carboxamide

N, N-dimethylformamide (10.00mL) containing 2, 6-dichloropyridine-3-carboxylic acid (1g, 5.208mmol) and carbonyldiimidazole (1.690g, 10.42mmol) was stirred at 50 ℃ for 1H a slurry of sodium hydride (312.5mg, 7.812mmol) in N, N-dimethylformamide was added to a solution of 1H-pyrazole-5-sulfonyl chloride (194.5mg, 1.16mmol, 1.5 equivalents) in N, N-dimethylformamide in a separate flask at room temperature and stirred for 30 min. The two mixtures were combined and stirred at room temperature for 1h the reaction mixture was poured onto ice and acidified to pH 2 by addition of 4M aqueous hydrochloric acid. The resulting mixture was extracted with ethyl acetate, the organic layer was dried over sodium sulfate, filtered, and the volatiles were removed by rotary evaporation. The crude material was purified by silica gel chromatography eluting with 10% methanol in dichloromethane to give 2, 6-dichloro-N- (1H-pyrazol-3-ylsulfonyl) pyridine-3-carboxamide (1.341g, 68%). ESI-MS M/z calculated 319.95377, Experimental 321.0(M +1) ⁺(ii) a Retention time: 0.34min (LC method A).

Step 2: 4- [3- [3- [ (2, 6-dichloropyridine-3-carbonyl) sulfamoyl ] pyrazol-1-yl ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To tert-butyl 2, 2-dimethyl-4- (3-methylsulfonyloxypropyl) pyrrolidine-1-carboxylate (300mg,0.894mmol) in N, N-dimethylformamide (6.00mL) was added 2, 6-dichloro-N- (1H-pyrazol-3-ylsulfonyl) pyridine-3-carboxamide (300mg, 0.934mmol) followed by cesium carbonate (875mg, 2.69 mmol) and the reaction mixture was stirred at 60 ℃ for 16H the reaction mixture was cooled to room temperature and poured into water (100 mL) and extracted with ethyl acetate (2 × 100mL) the combined organic layers were washed with water (2 × 100mL), dried (sodium sulfate), filtered and concentrated the resulting brown residue was purified by silica gel column chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate to give 4- [3- [3- [ (2, 6-dichloropyridine-3-carbonyl) sulfamoyl]Pyrazol-1-yl]Propyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (327mg, 65%);¹h NMR (400MHz, dimethylsulfoxide-d)₆)7.92(d, J ═ 8.0 Hz, 1H), 7.70(d, J ═ 2.2Hz, 1H), 7.51-7.46(M, 1H), 6.48(d, J ═ 2.3Hz, 1H), 4.14-4.05 (M, 2H), 3.53(dt, J ═ 14.7, 10.3Hz, 1H), 2.78-2.67(M, 1H), 2.08(dq, J ═ 11.7, 5.9, 5.3Hz, 1H), 1.39(s, 4H), 1.34(q, J ═ 11.5, 8.4Hz, 12H), 1.22(s, 3H), ESI-MS M/z calculated value 559.1423, experimental value 560.5(M +1) ⁺(ii) a Retention time: 0.71min (LC method A) and 4- [3- [5- [ (2, 6-dichloropyridine-3-carbonyl) sulfamoyl as a viscous colorless oil as the second regioisomer to be eluted]Pyrazol-1-yl]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (126mg, 25%);¹h NMR (400MHz, dimethylsulfoxide-d)₆)8.01(dd, J ═ 8.0, 5.0Hz, 1H), 7.95(s, 1H), 7.50(dd, J ═ 7.9, 1.5Hz, 1H), 7.37(d, J ═ 1.9Hz, 1H), 6.50(d, J ═ 1.9Hz, 1H), 4.34(t, J ═ 7.3Hz, 2H), 3.46(dt, J ═ 14.4, 9.9Hz, 1H), 2.66(td, J ═ 10.4, 4.7Hz, 1H), 1.99(s, 0H), 1.76(dt, J ═ 17.9, 8.3Hz, 3H), 1.38(d, J ═ 12.7, 9H), 1.30(d, J ═ 10.5, 3H), 17.9, 8.3Hz, 3H), 1.38 (calculated values of d, J ═ 12.7, 9H), 1.30(d, J ═ 10.5, 3H), 17.17 (calculated values of J ═ 3Hz, 1.5H), experimental M + 1.560 (calculated values of M, M⁺(ii) a Retention time: 0.74min (LC method A).

And step 3: 4-chloro-20, 20-dimethyl-10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Twenty-fourTwo carbon-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (compound A)

4- [3- [5- [ (2, 6-dichloropyridine-3-carbonyl) sulfamoyl group at room temperature]Pyrazol-1-yl]Propyl radical]A solution of tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (100mg, 0.1784mmol) in dichloromethane (2mL) and trifluoroacetic acid (150. mu.L, 1.960mmol) was stirred for 4h, the solvent was removed by evaporation, and 2M NH was added ₃Methanol (10mL) and the reaction mixture was stirred for 30min and then concentrated and dried in vacuo. The above residue was dissolved in dimethyl sulfoxide (2mL) and added

Molecular sieves and stirring the reaction mixture for 10min then cesium fluoride (85mg, 0.5596mmol) and potassium carbonate (78mg, 0.5644mmol) were added and the reaction mixture was heated at 140 ℃ overnight. The reaction mixture was filtered through a Whatman filter disc (puradisc 25 TF) and subjected to reverse phase HPLC-MS (Luna C sold by Phenomenex)₁₈(2) Column (75 × 30mM, 5 μm particle size) (pn: 00C-4252-U0-AX), and dual gradient run of 50% -99% mobile phase B over 15.0min, mobile phase a ═ water (5mM hydrochloric acid), mobile phase B ═ acetonitrile ═ 50mL/min, injection volume of 950 μ L, and column temperature of 25 ℃) to purify the filtrate, yielding 4-chloro-20, 20-dimethyl-10 λ as a white solid⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (28mg, 12%).¹H NMR (400MHz, chloroform-d) 8.77(s, 1H), 7.54-7.44 (m, 2H), 7.07(d, J ═ 2.3Hz, 1H), 6.48(d, J ═ 7.9Hz, 1H), 4.36-4.24(m, 1H), 4.06-3.85 (m, 1H), 2.67(t, J ═ 8.3Hz, 1H), 2.14(ddt, J ═ 17.7, 12.1, 6.2Hz, 2H), 2.07-2.01 (m, 1H), 1.98-1.84(m, 2H), 1.73(ddd, J ═ 12.1, 5.5, 1.5Hz, 1H), 1.55(s, 3H), 1.50(s, 3H), 1.44(t, 12.86, 0.86 (t, 0H), 1.86 (m, 0H). ESI-MS M/z calculated 423.1132, Experimental 424.4 (M) +1)⁺(ii) a Retention time: 1.76min (LC method B).

And 4, step 4: 4-chloro-21, 21-dimethyl-10 lambda⁶-thia-1, 3, 9, 14, 15-pentaazatetracyclo [17.2.1.02, 7.011, 15-]Docosac-2, 4, 6, 11, 13-pentaene-8, 10, 10-trione (Compound B)

4- [3- [3- [ (2, 6-dichloropyridine-3-carbonyl) sulfamoyl at room temperature]Pyrazol-1-yl]Propyl radical]A solution of tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (100mg, 0.1784mmol) in dichloromethane (2mL) and trifluoroacetic acid (150. mu.L, 1.960mmol) was stirred for 4 h. After completion of the reaction, the solvent was removed by evaporation and 2M NH-containing was added₃And the reaction mixture was stirred for 30min and concentrated, followed by vacuum drying the residue was dissolved in dimethyl sulfoxide (2mL) and added

Molecular sieves and stirring the reaction mixture for 10min subsequently cesium fluoride (85mg, 0.5596mmol) and potassium carbonate (78mg, 0.5644 mmol) are added and the reaction mixture is heated at 140 ℃ overnight the reaction mixture is filtered through a Whatman filter disc (puradisc 25 TF) and subjected to reverse phase HPLC-MS (Luna C sold by Phenomenex)₁₈(2) Column (75 × 30mM, 5 μm particle size) (pn: 00C-4252-U0-AX), and dual gradient run of 50% -99% mobile phase B over 15.0min, mobile phase a ═ water (5mM hydrochloric acid), mobile phase B ═ acetonitrile ═ 50 mL/min, injection volume of 950 μ L, and column temperature of 25 ℃) purified the filtrate to give 4-chloro-21, 21-dimethyl-10 λ as an off-white solid ⁶-thia-1, 3, 9, 14, 15-pentaazatetracyclo [17.2.1.02, 7.011, 15-]Docosac-2, 4, 6, 11, 13-pentaen-8, 10, 10-trione (10.2mg, 4%).¹H NMR (400MHz, chloroform-d) 9.16 (s, 1H), 7.76(d, J ═ 8.0Hz, 1H), 7.57(d, J ═ 2.1Hz, 1H), 7.35(d, J ═ 2.1Hz, 1H), 6.82(d, J ═ 8.0Hz, 1H), 4.78(dt, J ═ 13.8, 4.0Hz, 1H), 4.41-4.29(m, 1H), 3.20(t,j ═ 9.7Hz, 1H), 2.62-2.56(m, 1H), 2.52(s, 1H), 2.21-2.06(m, 1H), 1.91(s, 1H), 1.81-1.69(m, 3H), 1.63(s, 4H), 1.45(s, 3H). ESI-MS M/z calculated 423.1132, Experimental 424.4(M +1)⁺(ii) a Retention time: 1.9min (LC method B).

Example 119: preparation of 20, 20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl [)]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2 (7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (compound 32)

Step 1: 20, 20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2 (7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (compound 32)

4-chloro-20, 20-dimethyl-10 lambda is added at 140 DEG C⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docodeca-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (20mg, 0.04718 mmol), scandium trifluoromethanesulfonate, 3- [2- [1- (trifluoromethyl) cyclopropyl ] ketone]Ethoxy radical]A solution of-1H-pyrazole (31.16mg, 0.1415mmol) and NaH (9.435mg, 60% w/w, 0.2359mmol) in dimethylsulfoxide (2.0mL) was stirred for 16H. The reaction mixture was quenched with a few drops of water and filtered through a Whatman filter disc (puradisc 25 TF) and using the reverse phase HPLC-MS method with Luna C sold by Phenomenex₁₈(2) The filtrate was purified on a column (75 × 30mM, 5 μm particle size) (pn: 00C-4252-U0-AX) and by 15.0min of a dual gradient run of 1-99% mobile phase B (mobile phase a ═ water (5mM hydrochloric acid), mobile phase B ═ acetonitrile ═ 50mL/min and column temperature ═ 25 ℃) to give 20 as a white solid,20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosal-2 (7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (compound 32) (2.4 mg, 8%). ¹H NMR (400MHz, chloroform-d) 8.49(s, 1H), 8.17(d, J ═ 2.7Hz, 1H), 7.69 (d, J ═ 8.3Hz, 1H), 7.49(s, 1H), 7.08(d, J ═ 2.1Hz, 1H), 7.01(d, J ═ 8.2Hz, 1H), 5.87(d, J ═ 2.7Hz, 1H), 4.39(t, J ═ 7.1Hz, 2H), 4.35(s, 1H), 3.94(t, J ═ 12.9Hz, 1H), 2.78-2.72(m, 1H), 2.20-2.13(m, 2H), 2.10(d, J ═ 7.0Hz, 2H), 1.99(t, J ═ 3.10, 3.0H), 1.19 (m, 3.3H), 1H), 2.20-2.13(m, 2H), 2.10(d, J ═ 7.0Hz, 2H), 1.99(t, 3.3, 3.0H), 1H, 3.73 (m, 3.3.9H), 1H, 3.73 (m, 3.9H), 2H, 1H, 3.73 (m, 3.9H), 25, 3.9H), 3.9H, experimental value 608.6 (M +1)⁺(ii) a Retention time: 2.18min (LC method E).

Example 120: preparation of (15S) -12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracosane-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (compound 33) and (15R) -12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracosane-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (compound 34)

Step 1: (15S) -12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracosane-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (compound 33) and (15R) -12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18 ].3.1.05，10.011，15]Tetracosane-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (compound 34)

Racemic 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] 8 using ChiralPak AS-H (250X 10mm column, 5 μm particle size) and 18% acetonitrile: methanol (90: 10; no modifier)/82% carbon dioxide mobile phase (10mL/min)]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Chiral SFC chromatography of tetracosane-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (90mg, 0.1420mmol) gave (15S) -12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl-n-propyl ] as the first enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -2 lambda ⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracos-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (compound 33) (28.6mg, 64%);¹h NMR (400MHz, dimethylsulfoxide-d)₆) 12.73(s, 1H), 8.23(d, J ═ 2.8Hz, 1H), 8.01(d, J ═ 8.3Hz, 1H), 7.58(t, J ═ 7.8Hz, 1H), 7.29(t, J ═ 6.2Hz, 1H), 7.03(d, J ═ 7.2Hz, 2H), 6.63(d, J ═ 8.4Hz, 1H), 6.13(d, J ═ 2.8Hz, 1H), 4.32(t, J ═ 6.9Hz, 2H), 3.72(s, 2H), 3.10(s, 1H), 2.11-2.05(M, 2H), 1.85(s, 2H), 1.74(d, J ═ 8.9, 2H), 1.43(d, 65, J ═ 6.11-2.05 (M, 2H), 1.85(s, 2H), 1.74(d, J ═ 8.9, 2H), 1.43(d, 6, J ═ 8.84, 1H), M-3585 (M, M + 7 (M⁺(ii) a Retention time: 1.85min (LC method B) and (15R) -12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as the second enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracos-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (compound 34) (29.1mg, 65%);¹h NMR (400MHz, dimethylsulfoxide-d)₆)12.73(s，1H)，8.23(d，J＝2.8 Hz，1H)，8.01(d，J＝8.2Hz，1H)，7.58(dd, J ═ 8.4, 7.2Hz, 1H), 7.29(d, J ═ 6.9Hz, 1H), 7.03(d, J ═ 7.2Hz, 2H), 6.63(d, J ═ 8.4Hz, 1H), 6.13(d, J ═ 2.8Hz, 1H), 4.38-4.28 (M, 2H), 3.72(s, 2H), 3.10(s, 1H), 2.08(t, J ═ 7.0Hz, 2H), 1.96-1.68(M, 4H), 1.51(s, 5H), 1.35(s, 4H), 0.99-0.85(M, 5H), ESI-MS M/z calculated value 633.2345, experimental value 634.2(M +1) ⁺(ii) a Retention time: 1.85min (LC method B).

Example 121: preparation of 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 20, 25-pentaazatetracyclo [19.3.1.05, 10.011, 15 [ ]]Pentacosac-1 (24), 5, 7, 9, 21(25), 22-hexaen-2, 2, 4-trione (compound 37)

Step 1: 5- (3-Cyanopropyl) 2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To a round bottom flask was added tert-butyl 2, 2-dimethyl-5- (3-methylsulfonyloxypropyl) pyrrolidine-1-carboxylate (650mg, 1.938mmol), dimethyl sulfoxide (2mL), and sodium cyanide (100mg, 2.041mmol). The reaction was heated at 80 deg.C overnight, the reaction was filtered and purified by HPLC (1% -99% acetonitrile/water + 0.1% hydrochloric acid modifier) to give tert-butyl 5- (3-cyanopropyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (272mg, 53%). ESI-MS M/z calculated 266.19943, experimental 211.2(M +1)⁺(ii) a Retention time: 1.67min (LC method B).

Step 2: 5- (4-Aminobutyl) -2, 2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester

Adding 5- (3) into a round-bottom flask-cyanopropyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (271 mg, 1.017mmol), methanol (1.50mL), raney nickel (100mg 50% weight/volume) and ammonia (2.80mL, 7M, 19.60mmol). the reaction was purged with nitrogen and a hydrogen balloon (2.050mg, 1.017mmol) attached and the mixture stirred at room temperature overnight. Raney nickel (100mg 50% w/v) and ammonia (2.80mL, 7M, 19.60mmol) were additionally added and the reaction was stirred for 4h. the reaction was filtered and the filter cake was washed with additional methanol and dichloromethane the filtrate solution was evaporated to dryness to afford tert-butyl 5- (4-aminobutyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (270mg, 98%) as a clear colorless oil, calculated ESI-MS M/z 270.23074, experimental 271.3(M +1) ⁺(ii) a Retention time: 1.1min (LC method B).

And step 3: 2, 2-dimethyl-5- [4- [ (6-sulfamoyl-2-pyridyl) amino ] butyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

To a vial was added potassium carbonate (415mg, 3.003mmol), 6-fluoropyridine-2-sulfonamide (170mg, 0.9650mmol) and a solution of tert-butyl 5- (4-aminobutyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (270mg, 0.9985mmol) in dimethyl sulfoxide (3mL), the reaction was placed in a pre-heated 80 ℃ oil bath and stirred overnight, the reaction was filtered and purified by HPLC (1% -99% acetonitrile/water + 0.1% hydrochloric acid modifier) to provide 2, 2-dimethyl-5- [4- [ (6-sulfamoyl-2-pyridyl) amino]Butyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (155.2mg, 38%). ESI-MS M/z calculated 426.23007, Experimental value 427.3(M +1)⁺(ii) a Retention time: 1.71min (LC method B).

And 4, step 4: 5- [4- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] butyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

Adding 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] to a round bottom flask]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (166.0mg, 0.4418mmol), carbonyldiimidazole (71mg, 0.4379mmol) and tetrahydrofuran (2.0 mL.) the reaction was heated to 45 ℃ for 2h, followed by addition of 2, 2-dimethyl-5- [4- [ (6-sulfamoyl-2-pyridyl) amino ]Butyl radical]A solution of pyrrolidine-1-carboxylic acid tert-butyl ester (155.2mg, 0.3638mmol) in tetrahydrofuran (2.0mL) was added followed by 1, 8-diazabicyclo [5.4.0]Undec-7-ene (165 μ L, 1.103 mmol) and the reaction was stirred at room temperature overnight. The reaction was filtered and purified by HPLC (30% -99% acetonitrile/water + 0.1% hydrochloric acid modifier) to give 5- [4- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] methyl ] propyl ] separated as a white solid]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Butyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (126mg, 44%). ESI-MS M/z calculated 783.27924, Experimental 784.5(M +1)⁺(ii) a Retention time: 1.9min (LC method G).

And 5: 2-chloro-N- [ [6- [4- (5, 5-dimethylpyrrolidin-2-yl) butylamino ] -2-pyridinyl ] sulfonyl ] -6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide

Adding 5- [4- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] to a round bottom flask]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Butyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (126mg, 0.1607mmol), dichloromethane (2mL) and hydrochloric acid (400 μ L, 4M in dioxane, 1.600mmol) _ stir reaction at room temperature for 1h quench the reaction with saturated sodium bicarbonate and extract with ethyl acetate the organic layer is dried over sodium sulfate, filtered and evaporated to afford 2-chloro-N- [ [6- [4- (5, 5-dimethylpyrrolidin-2-yl) butylamino ]-2-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (105mg, 96%). ESI-MS calculated m/z 683.2268, experimentValue 684.5(M +1)⁺(ii) a Retention time: 0.79min (LC method B).

Step 6: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 20, 25-pentaazatetracyclo [19.3.1.05, 10.011, 15 [ ]]Pentacosac-1 (24), 5, 7, 9, 21(25), 22-hexaen-2, 2, 4-trione (compound 37)

To a vial were added potassium carbonate (107mg, 0.7742mmol), cesium fluoride (35mg, 0.2304mmol) and 2-chloro-N- [ [6- [4- (5, 5-dimethylpyrrolidin-2-yl) butylamino]-2-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]A solution of pyridine-3-carboxamide (105mg, 0.1535 mmol) in dimethylsulfoxide (1.8mL) the reaction was heated in a sealed tube at 150 ℃ overnight. The reaction was quenched with brine and extracted with ethyl acetate the organic layer was dried over sodium sulfate, filtered and evaporated. The crude product was purified by HPLC (30% -99% acetonitrile/water + 0.1% hydrochloric acid modifier) to give 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] amine ]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 20, 25-pentaazatetracyclo [19.3.1.05, 10.011, 15 [ ]]Pentacosan-1 (24), 5, 7, 9, 21(25), 22-hexaen-2, 2, 4-trione (compound 37) (27mg, 25%). ESI-MS M/z calculated 647.2502, Experimental 648.2(M +1)⁺(ii) a Retention time: 1.97min (LC method B).

Example 122: preparation of 8- (3-hydroxy-1H-pyrazol-1-yl) -12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (hydrochloride) (Compound 38)

Step 1: 4- [3- [ [6- [ [ 2-chloro-6- [3- [ (2, 2, 3, 3-tetramethylcyclopropyl) methoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- [ (2, 2, 3, 3-tetramethylcyclopropyl) methoxy group]Pyrazol-1-yl]Pyridine-3-carboxylic acid (200mg, 0.5431mmol) and carbonyldiimidazole (88.06mg, 0.5431mmol) were combined in tetrahydrofuran (2mL) and stirred at 50 ℃ for 90min, then 2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (179.3mg, 0.4345mmol) followed by the addition of 1, 8-diazabicyclo [5.4.0 ]Undec-7-ene (124.0mg, 121.8 μ L, 0.8147mmol) and the reaction was heated at 50 ℃ for 18 h. The organics were separated, dried over sodium sulfate, filtered and evaporated, followed by chromatography on silica gel using a gradient of 100% hexane to 70% ethyl acetate/hexane to give 4- [3- [ [6- [ [ 2-chloro-6- [3- [ (2, 2, 3, 3-tetramethylcyclopropyl) methoxy ] as a white solid]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (206mg, 51%). ESI-MS calculated M/z 743.3232, Experimental 744.7(M +1)⁺(ii) a Retention time: 0.95min (LC method A).

Step 2: 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-3-yl) propylamino ] -2-pyridinyl ] sulfonyl ] -6- (3-hydroxypyrazol-1-yl) pyridine-3-carboxamide

To 4- [3- [ [6- [ [ 2-chloro-6- [3- [ (2, 2, 3, 3-tetramethylcyclopropyl) methoxy group at 0 deg.C]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical](iii) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (25 mg, 0.03359mmol) in dichloromethane (1mL) was added trifluoroacetic acid 19.16mg, 12.95 μ L, 0.1680mmol), and the mixture was stirred for 30min (reaction mixture 1). Separately, 4- [3- [ [6- [ [ 2-chloro-6- [3- [ (2, 2, 3, 3-tetramethylcyclopropyl) methoxy group is added at 0 deg.C]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (25mg, 0.03359mmol) in dioxane (1mL) hydrochloric acid (42.00 μ L, 4M, 0.1680mmol) was added and the mixture was stirred for 30min (reaction mixture 2) separately, 4- [3- [ [6- [ [ [ 2-chloro-6- [3- [ [ (2, 2, 3, 3-tetramethylcyclopropyl) methoxy ] was added separately]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]A solution of tert-butyl (2, 2-dimethyl-pyrrolidine-1-carboxylate (25mg, 0.03359mmol) in 2, 2, 2-trifluoroethanol (1.680g, 1.224mL, 16.79mmol) containing 1% trifluoroacetic acid was stirred for 30min (reaction mixture 3) separately to 4- [3- [ [6- [ [ [ 2-chloro-6- [3- [ (2, 2, 3, 3-tetramethylcyclopropyl) methoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]To a solution of tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (25mg, 0.03359mmol) in toluene (1mL) was added silica gel (100mg) and the mixture was heated at 90 ℃ for 24h (reaction mixture 4). All four reaction mixtures were combined and subjected to the reverse phase HPLC-MS method using Luna C sold by Phenomenex ₁₈(2) Column (75 × 30mM, 5 μm particle size) (pn: 00C-4252-U0-AX) and purification by 15.0min of a two gradient run of 20% -80% mobile phase B (mobile phase a ═ water (5mM hydrochloric acid), mobile phase B ═ acetonitrile, flow rate ═ 50mL/min, injection volume ═ 950 μ L and column temperature ═ 25 ℃) afforded 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-3-yl) propylamino]-2-pyridyl]Sulfonyl radical]-6- (3-hydroxypyrazol-1-yl) pyridine-3-carboxamide (42mg, 47%).¹H NMR (400MHz, methanol-d)₄)8.31(d，J＝2.9Hz，1H)，8.00(d，J＝8.4Hz，1H)，7.72-7.63(m，2H)，7.30(dd， J＝7.2，0.8Hz，1H)，6.84(dd，J＝8.6，0.8Hz，1H)，5.97(d，J＝2.8Hz，1H)，3.50(dd， J＝11.8，8.4Hz，21H)，3.41(dp，J＝20.3，6.7Hz，2H)，2.93(dd，J＝11.8，9.1Hz，1H)， 2.54(dt，J＝16.6，8.3Hz，1H)，2.09(dd，J＝13.1，7.5Hz，1H)，1.70-1.59(m，2H)，1.59-1.48(m，2H)，1.45(s，3H)，1.37(s，3H) In that respect ESI-MS M/z calculated 533.1612, Experimental 534.5(M +1)⁺(ii) a Retention time: 0.45min (LC method A).

And step 3: 8- (3-hydroxy-1H-pyrazol-1-yl) -12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (hydrochloride) (Compound 38)

To 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-3-yl) propylamino]-2-pyridyl]Sulfonyl radical]To a solution of (E) -6- (3-hydroxypyrazol-1-yl) pyridine-3-carboxamide (42mg, 0.07865mmol) in dimethyl sulfoxide (2.0mL) was added

Molecular sieves and the mixture stirred at room temperature for 15min then cesium fluoride (11.95 mg, 0.07865mmol) and potassium carbonate (10.87mg, 0.07865mmol) were added and the reaction mixture was heated at 140 ℃ overnight the reaction mixture was filtered through a Whatman filter disc (puradisc 25 TF) and by reverse phase HPLC-MS method using Luna C sold by Phenomenex ₁₈(2) The filtrate was purified by dual gradient run of a column (75 × 30mM, 5 μm particle size) (pn: 00C-4252-U0-AX) and 30% -80% mobile phase B over 15.0min (mobile phase a ═ water (5mM hydrochloric acid), mobile phase B ═ acetonitrile, flow rate 50mL/min, injection volume 950 μ L and column temperature 25 ℃) to give 8- (3-hydroxy-1H-pyrazol-1-yl) -12, 12-dimethyl-2 λ as a white solid⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (hydrochloride) (compound 38) (2.5mg, 17%).¹H NMR (400MHz, methanol-d)₄)8.21(d，J＝2.7Hz，1H)，7.84(d，J＝8.2Hz，1H)，7.57-7.51 (m，1H)，7.16(d，J＝7.2Hz，1H)，6.92(d，J＝8.3Hz，1H)，6.67(d，J＝8.5Hz，1H)， 5.87(d，J＝2.7Hz，1H)，4.10-4.00(m，1H)，3.66-3.49(m，1H)，3.09-3.00(m，1H)， 2.90-2.82(M, 1H), 2.66(d, J ═ 11.1Hz, 1H), 2.24-2.12(M, 1H), 1.92-1.82(M, 1H), 1.66(s, 3H), 1.59(s, 3H), 1.49-1.39(M, 2H), 0.95-0.83(M, 2H), ESI-MS M/z calculated 497.1845, experimental 498.5(M +1)⁺(ii) a Retention time: 1.48min (LC method E).

Example 123: preparation of 21, 21-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ] -]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 23-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaene-8, 10, 10-trione (compound 39)

Step 1: 2, 2-dimethyl-4- [4- (3-sulfamoylpyrazol-1-yl) butyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

Tert-butyl 2, 2-dimethyl-4- (4-methylsulfonyloxybutyl) pyrrolidine-1-carboxylate (848mg, 2.426mmol) and 1H-pyrazole-3-sulfonamide (361.5mg, 2.457mmol) were dissolved in N, N-dimethylformamide (9.0mL), followed by potassium carbonate (1.2g, 8.683mmol) and stirred in a sealed 20mL vial at 60 ℃ for 20H (UPLC indicates conversion to the same mass of the desired product, which is the minor regioisomeric by-product plus the minor, lower polarity second peak), cooled to room temperature, poured into water (100mL) and extracted with ethyl acetate (2 × 100mL), the organic layers combined, washed with water (2 × 100mL), dried (sodium sulfate), filtered and concentrated. The brown residue was purified by silica gel chromatography using a gradient of 100% hexane to 100% ethyl acetate to give 2, 2-dimethyl-4- [4- (3-sulfamoylpyrazol-1-yl) butyl ] as a colorless oil]Pyrrolidine-1-carboxylic acid tert-butyl ester (427mg, 44%) which turned into a white solid under vacuum.¹H NMR (400MHz, dimethylsulfoxide-d)₆)7.87(d，J＝2.3Hz，1H)，7.37(s，2H)，6.56(d，J＝2.3Hz， 1H) 4.15(t, J ═ 7.1Hz, 2H), 3.53(dd, J ═ 11.2, 5.4Hz, 1H), 2.76(dd, J ═ 22.3, 10.8 Hz, 1H), 2.05(s, 1H), 1.94-1.83(m, 1H), 1.82-1.73(m, 2H), 1.40-1.35(m, 12H), 1.33(s, 3H), 1.30(d, J ═ 2.5Hz, 1H), 1.23(s, 4H). ESI-MS M/z calculated 400.21442, Experimental 401.2(M +1) ⁺(ii) a Retention time: 1.64min (LC method E).

Step 2: 4- [4- [3- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] pyrazol-1-yl ] butyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (500mg, 1.331mmol) and carbonyldiimidazole (215mg, 1.326mmol) were combined in tetrahydrofuran (8.0mL) and stirred at 50 ℃ for 120min, then 2, 2-dimethyl-4- [4- (3-sulfamoylpyrazol-1-yl) butyl ] was added]Pyrrolidine-1-carboxylic acid tert-butyl ester (423mg, 1.056mmol) followed by addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (350 μ L, 2.340mmol) and the reaction heated at 50 ℃ for 20 h.the reaction mixture was diluted with ethyl acetate and washed with 1M citric acid solution followed by brine the organics were separated, dried over sodium sulfate, filtered and evaporated and then purified by silica gel chromatography using a gradient of 100% hexane to 90% ethyl acetate/hexane to give 4- [4- [3- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Pyrazol-1-yl ]Butyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (587mg, 73%). ESI-MS M/z calculated 757.2636, experimental 758.2(M +1)⁺(ii) a Retention time: 2.37min (LC method E).

And step 3: 21, 21-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 23-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaene-8, 10, 10-trione (compound 39)

4- [4- [3- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] group]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Pyrazol-1-yl]Butyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (580mg, 0.7649 mmol) was dissolved in dichloromethane (12mL) and hydrochloric acid (6.0mL, 4M in dioxane, 24.00mmol) was added to the mixture and stirred at room temperature for 1 h. The mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate and then added with 2M aqueous sodium carbonate (5mL) to bring the pH to about 10, the organic layer was removed and the aqueous layer was further washed with ethyl acetate (2X 10mL), the organic layers were combined, washed with brine, then dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure, this material and potassium carbonate (550mg, 3.980mmol), cesium fluoride (185mg, 1.218mmol),

Molecular sieves and dimethylsulfoxide (12mL) were combined in a vial, purged with nitrogen, capped, heated to 150 ℃ and stirred for 18 h. Cool to room temperature and dilute the reaction with ethyl acetate and wash with 1M citric acid solution, followed by brine. The organics were separated, dried over sodium sulfate, filtered and evaporated, then purified by silica gel chromatography using a gradient of 100% hexane to 80% ethyl acetate/hexane to give 21, 21-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 23-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaen-8, 10, 10-trione (compound 39) (176.9mg, 37%).¹H NMR (400 MHz, dimethylsulfoxide-d)₆)12.59(s，1H)，8.21(d，J＝2.8Hz，1H)，7.99(d，J＝2.1Hz，1H)， 7.77(d，J＝8.3Hz，1H)，6.97-6.81(m，2H)，6.12(d，J＝2.7Hz，1H)，4.30(dd，J＝ 15.9，9.0Hz，4H)，2.73(dt，J＝22.6，11.0Hz，2H)，2.31-2.18(m，1H)，2.18-2.03(m， 3H)，2.02-1.92(m，1H)，1.89(dd，J＝11.9，5.5Hz, 1H), 1.67(s, 1H), 1.61(s, 3H), 1.60-1.54(m, 1H), 1.52(s, 3H), 1.48(d, J ═ 12.4Hz, 1H), 1.16-1.03(m, 1H), 0.99-0.93 (m, 2H), 0.90(d, J ═ 10.9Hz, 2H), 0.77(s, 1H). ESI-MS M/z calculated 621.2345, Experimental 622.4(M +1)⁺(ii) a Retention time: 2.2min (LC method E).

Example 124: preparation of 7, 7-dimethyl-11- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ] ]Ethoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.04, 8.09, 14]Docosac-1 (22), 9, 11, 13, 18, 20-hexaen-15, 17, 17-trione (Compound 41)

Step 1: 5, 5-dimethyl-1-trimethylsilyloxy-pyrrolidine-2-carbonitrile

Trimethylsilylcarbonitrile (30.93g, 39mL, 311.8mmol) was added to dichloromethane (920mL) containing 2, 2-dimethyl-1-oxoanion (oxido) -3, 4-dihydropyrrol-1-ium (23.31g, 206.0mmol) and the mixture was left to stir at room temperature overnight the reaction mixture was concentrated under reduced pressure under safe conditions to afford the desired product 5, 5-dimethyl-1-trimethylsilyloxy-pyrrolidine-2-carbonitrile (44.04g, 101%) as a crude amber oil which was used directly in the next step. ESI-MS M/z calculated 212.13, Experimental 213.2(M +1)⁺(ii) a Retention time: 2.325min (LC method I).

Step 2: 1-hydroxy-5, 5-dimethyl-pyrrolidine-2-carboxamide

5, 5-dimethyl-1-trimethylsilyloxy-pyrrolidine-2-carbonitrile (13g, 61.22mmol) was slowly addedSlowly added to sulfuric acid (160.1g, 87mL, 1.632mol), cooled with an ice bath, and kept stirring at room temperature for 3h, the reaction mixture was diluted with ice (400mL), and the resulting mixture was slowly neutralized in 3 portions with solid sodium hydroxide (125g, 3.125mol) (the last two portions were dissolved in water (75 mL)) and the pH verified to be weakly basic to neutral the mixture was extracted with ethyl acetate (3 × 500 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure, followed by vacuum drying to provide the desired product 1-hydroxy-5, 5-dimethyl-pyrrolidine-2-carboxamide as a pale yellow powder (8.51g, 88%). ¹H NMR (300MHz, dimethylsulfoxide-d)₆) ppm 0.92(s, 3H), 1.07(s, 3H), 1.38-1.59(M, 3H), 1.91-2.09(M, 1H), 3.13-3.22 (M, 1H), 6.92(br.s., 1H), 7.08(br.s., 1H), 7.62(s, 1H), ESI-MS M/z calculated 158.198, experimental 159.2(M +1)⁺(ii) a Retention time: 1.561min (LC method I).

And step 3: 5, 5-dimethylpyrrolidine-2-carboxamide

1-hydroxy-5, 5-dimethyl-pyrrolidine-2-carboxamide (8.51g, 53.79mmol) dissolved in methanol (200mL) was stirred with Raney nickel (8.7g, 148.2mmol) and hydrogen from an inflated balloon with a gas capacity of 8L overnight after 5h more Raney nickel (8g, 136.3mmol) was added and the mixture was stirred overnight additional Raney nickel (9.69g, 165.1mmol) was put into the mixture and the mixture was further stirred over 3 days. More raney nickel (9.5g, 161.9mmol) was added to the reaction mixture and the mixture was stirred for 4h the reaction mixture was decanted and the nickel solid washed with methanol (3 x 250mL) and some celite was added to the combined methanol fractions, followed by filtration through celite and washing of the filter cake with methanol. The combined filtrates were concentrated under reduced pressure to provide the desired product 5, 5-dimethylpyrrolidine-2-carboxamide as a beige solid (7.29g, 95%). ¹H NMR (300MHz，CDCl₃)ppm 1.16(s，3H)，1.19(s，3H)，1.45-1.72(m，2H)，1.81(br.s.，1H)， 1.92-2.09(m1H), 2.18-2.40(M, 1H), 3.78(dd, J ═ 9.4, 6.2Hz, 1H), 5.70(br.s., 1H), 7.45(br.s., 1H), ESI-MS M/z calculated 142.1106, experimental 143.2(M +1)⁺(ii) a Retention time: 0.31min (LC method I).

And 4, step 4: 5-carbamoyl-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

Di-tert-butyl dicarbonate (21g, 96.22mmol) was added to 5, 5-dimethylpyrrolidine-2-carboxamide (7.25g, 50.98mmol) dissolved in dioxane (140mL), and water (50mL) was added to the mixture, followed by stirring the mixture at room temperature overnight. Sodium hydroxide (1.84 g, 46.00mmol) dissolved in water (100mL) was added to the mixture and the mixture was kept under stirring for 2min, followed by the addition of ethyl acetate (200mL) and the aqueous phase discarded the organic fraction was dried over anhydrous magnesium sulfate, filtered, then concentrated under reduced pressure the resulting oil was partially solidified after standing under vacuum the solid was triturated in heptane (50mL), filtered and washed with more heptane (3 x 100mL), followed by vacuum drying to afford 5-carbamoyl-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a white powder (10.95g, 89%).¹H NMR(300MHz，CDCl₃) ppm 1.33(br.s., 3H), 1.48(br.s., 12H), 1.70-2.34(M, 4H), 4.16-4.48(M, 1H), 5.30-5.58(M, 1H), 5.71-7.03(M, 1H), ESI-MS M/z calculated 242.163, experimental 143.2 ═ (M +1-Boc) ⁺(ii) a Retention time: 1.67min (LC method I).

And 5: 5- (aminomethyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

5-carbamoyl-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (5.3g, 21.87mmol) was added to borane-tetrahydrofuran (102mL, 1M in tetrahydrofuran, 102.0mmol) and after hydrogen evolution ceased, the reaction was allowed to reactThe mixture was heated to 70 ℃ overnight. The reaction mixture was slowly quenched with concentrated ammonium chloride (1 mL.) this mixture was then transferred to a 1L round bottom flask containing deionized water (110 mL.) iodine (100mg, 0.020mL, 0.394mmol) was added with vigorous stirring and the mixture was left to stir exposed to air for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified on silica gel using a gradient of 10% to 100% methanol/dichloromethane other materials were recovered by applying ammonium hydroxide (2mL) on top of the column followed by elution with pure methanol (3 ×). this afforded tert-butyl 5- (aminomethyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (1.19g, 24%) as an amber oil.¹H NMR(300MHz，CDCl₃) ppm 1.27(br.s., 3H), 1.33-1.51(m, 14H), 1.62-1.76(m, 2H), 1.78-2.03(m, 2H), 2.53(dd, J ═ 12.6, 8.2Hz, 1H), 2.73-3.00(m, 1H), 3.61-3.99(m, 1H). ESI-MS M/z calculated 228.331, Experimental 229.3(M +1) ⁺(ii) a Retention time: 1.33min (LC method I).

Step 6: 2, 2-dimethyl-5- [ [ (6-sulfamoyl-2-pyridyl) amino ] methyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

To 5- (aminomethyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (140mg, 0.6131mmol) and 6-fluoropyridine-2-sulfonamide (108.0mg, 0.6131mmol) in dimethylsulfoxide (1.179mL) was added potassium carbonate (86.43mg, 0.6254mmol) and the mixture was stirred at 100 ℃ for 20h, then allowed to cool to room temperature, diluted with ethyl acetate and poured into 1M citric acid. The layers were separated, then the organic layer was washed with saturated brine solution, dried (sodium sulfate), filtered and concentrated to a yellow foam which was purified by silica gel chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate to give 2, 2-dimethyl-5- [ [ (6-sulfamoyl-2-pyridinyl) amino ] as a white solid]Methyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (115.6mg, 49%). ESI-MS M/z calculated 384.18314, Experimental 385.4(M +1)⁺(ii) a Retention time: 0.62min (LC method A).

And 7: 5- [ [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] methyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

In a 20mL vial, 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (113.0mg, 0.3007mmol) and carbonyldiimidazole (53.44mg, 0.3296mmol) were combined in tetrahydrofuran (1.659mL) and stirred loose at 50 ℃ for 120min, then, 2-dimethyl-5- [ [ (6-sulfamoyl-2-pyridyl) amino group-containing solution was added]Methyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (115.6mg, 0.3007mmol) in tetrahydrofuran (2.213mL) followed by the addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (94.25 mg, 92.58 μ L, 0.6191mmol) and the reaction was heated at 50 ℃ for 16h₁₈(2) Column (75 × 30mM, 5 μm particle size) (pn: 00C-4252-U0-AX) and purification by 15.0 min of dual gradient run of 30% -99% mobile phase B (mobile phase a ═ water (5mM hydrochloric acid), mobile phase B ═ acetonitrile, flow rate ═ 50mL/min, injection volume ═ 950 μ L and column temperature ═ 25 ℃) afforded 5- [ [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] -6- [3 ] ]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Methyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (119.2mg, 53%). ESI-MS M/z calculated 741.2323, Experimental 742.2(M +1)⁺(ii) a Retention time: 0.88min (LC method A).

And 8: 2-chloro-N- [ [6- [ (5, 5-dimethylpyrrolidin-2-yl) methylamino ] -2-pyridinyl ] sulfonyl ] -6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide

Reacting 5- [ [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] group]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Methyl radical]Tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (119.2mg, 0.1606mmol) was dissolved in dichloromethane (520.2 μ L) and trifluoroacetic acid (840.1mg, 567.6 μ L, 7.368mmol) was added to the mixture and the resulting mixture was stirred at room temperature for 60 min. The mixture was concentrated to dryness under reduced pressure, redissolved in dichloromethane and hexane (1: 1), and then the material was evaporated to dryness under reduced pressure and placed under vacuum overnight to give 2-chloro-N- [ [6- [ (5, 5-dimethylpyrrolidin-2-yl) methylamino]-2-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical ]Pyrazol-1-yl]Pyridine-3-carboxamide (92.9mg, 90%). ESI-MS M/z calculated 641.1799, Experimental 642.2(M +1)⁺(ii) a Retention time: 0.63min (LC method A).

And step 9: 7, 7-dimethyl-11- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.04, 8.09, 14]Docosac-1 (22), 9, 11, 13, 18, 20-hexaen-15, 17, 17-trione (Compound 41)

To 2-chloro-N- [ [6- [ (5, 5-dimethylpyrrolidin-2-yl) methylamino]-2-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]To a solution of pyridine-3-carboxamide (92.9mg, 0.1447mmol) in dimethyl sulfoxide (3.716mL) were added potassium carbonate (99.99mg, 0.7235 mmol), CsF (26.37mg, 0.1736mmol) and a small amount

The resulting mixture was capped and heated to 150 ℃ and stirred overnight. Cooled to room temperature, filtered and treated with Luna C sold by Phenomenex using reverse phase HPLC-MS method₁₈(2) Column (75 × 30mm, 5 μm particle size)) pn: 00C4252-U0-AX) and purified over 15.0min of a dual gradient run of 30% -99% mobile phase B (mobile phase a ═ water (5mM hydrochloric acid), mobile phase B ═ acetonitrile, flow rate 50mL/min, injection volume of 950 μ L and column temperature of 25 ℃). The product containing fractions were combined, acetonitrile removed by rotary evaporation, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate (1 ×), dried (sodium sulfate), filtered and concentrated to 7, 7-dimethyl-11- (3- {2- [1- (trifluoromethyl) cyclopropyl) as a white solid ]Ethoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.04, 8.09, 14]Docosac-1 (22), 9, 11, 13, 18, 20-hexaen-15, 17, 17-trione (compound 41) (27.6mg, 31%). ESI-MS M/z calculated 605.2032, Experimental 606.0(M +1)⁺(ii) a Retention time: 1.89min (LC method B).

Example 125: preparation of 21, 21-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ] -]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 23-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaen-8, 10, 10-trione (enantiomer 1) (compound 44) and 21, 21-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 23-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 45)

Step 1: 21, 21-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 23-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaen-8, 10, 10-trione (enantiomer 1) (compound 44) and 21, 21-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 23-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaene-8, 10, 10-trieneKetone (enantiomer 2) (Compound 45)

Racemic 21, 21-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] 2-methanol using ChiralPak AS-H (250X 21.2mm column, 5 μm particle size) and a 25% acetonitrile: methanol (90: 10)/75% carbon dioxide mobile phase (70mL/min)]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 23-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaen-8, 10, 10-trione (160mg, 0.2548 mmol) was subjected to chiral SFC chromatography to give 21, 21-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl-4 ] as a white solid of the first enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 23-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaen-8, 10, 10-trione (enantiomer 1) (compound 44) (65.8mg, 82%); ESI-MS M/z calculated 621.2345, Experimental 622.4(M +1)⁺(ii) a Retention time: 2.2min (LC method E), and 21, 21-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid of the second enantiomer to be eluted ]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 23-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaen-8, 10, 10-trione (enantiomer 2) (compound 45) (70.8mg, 89%);¹h NMR (400MHz, dimethyl sulfoxide-d 6)12.59(s, 1H), 8.21(d, J ═ 2.8Hz, 1H), 7.99(s, 1H), 7.77(d, J ═ 7.2Hz, 1H), 7.02-6.80(m, 2H), 6.12(d, J ═ 2.7Hz, 1H), 4.44-4.19(m, 4H), 2.70(d, J ═ 21.3Hz, 2H), 2.20(s, 1H), 2.08(t, J ═ 7.1Hz, 2H), 2.00(d, J ═ 6.6Hz, 1H), 1.89(dd, J ═ 11.9, 5.6Hz, 1H), 1.67(d, J ═ 5.7, 1H), 1.61 (s, 3H), 1.53 (s, 1H), 1.3H, 1H, 1.3 (s, 3H), 1H, 3(m ═ 3H, 1H, 3H, 1H, 3H, 1, experimental value 622.4(M +1)⁺(ii) a Retention time: 2.2min (LC formula)Method E).

Example 126: preparation of 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 20, 25-pentaazatetracyclo [19.3.1.05, 10.011, 15 [ ]]Pentacosac-1 (24), 5, 7, 9, 21(25), 22-hexaen-2, 2, 4-trione (enantiomer 1) (compound 46) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 20, 25-pentaazatetracyclo [19.3.1.05, 10.011, 15 [ ]]Pentacosac-1 (24), 5, 7, 9, 21(25), 22-hexaen-2, 2, 4-trione (enantiomer 2) (compound 47)

Step 1: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 20, 25-pentaazatetracyclo [19.3.1.05, 10.011, 15 [ ]]Pentacosac-1 (24), 5, 7, 9, 21(25), 22-hexaen-2, 2, 4-trione (enantiomer 1) (compound 46) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 20, 25-pentaazatetracyclo [19.3.1.05, 10.011, 15 [ ]]Pentacosac-1 (24), 5, 7, 9, 21(25), 22-hexaen-2, 2, 4-trione (enantiomer 2) (compound 47)

A ChiralPak AS-H (250X 10mm column, 5 μm particle size) and 18% acetonitrile: methanol (90: 10; no modifier))/82% carbon dioxide mobile phase (10mL/min) pair of 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] was used]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 20, 25-pentaazatetracyclo [19.3.1.05, 10.011, 15 [ ]]The pentacosan-1 (24), 5, 7, 9, 21(25), 22-hexaen-2, 2, 4-trione (23mg, 0.03320mmol) was subjected to chiral SFC chromatography to give the first enantiomer to be eluted Constitutional 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl)]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 20, 25-pentaazatetracyclo [19.3.1.05, 10.011, 15 [ ]]Pentacosac-1 (24), 5, 7, 9, 21(25), 22-hexaen-2, 2, 4-trione (enantiomer 1) (compound 46) (6.9mg, 64%); ESI-MS M/z calculated 647.2502, Experimental 648.3(M +1)⁺(ii) a Retention time: 1.97min (LC method B), and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as the second enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 20, 25-pentaazatetracyclo [19.3.1.05, 10.011, 15 [ ]]Pentacosac-1 (24), 5, 7, 9, 21(25), 22-hexaen-2, 2, 4-trione (enantiomer 2) (compound 47) (6.8mg, 63%); ESI-MS M/z calculated 647.2502, Experimental 648.3(M +1)⁺(ii) a Retention time: 1.97min (LC method B).

Example 127: preparation of 7, 7-dimethyl-11- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.04, 8.09, 14]Docosac-1 (22), 9, 11, 13, 18, 20-hexaen-15, 17, 17-trione (enantiomer 1) (compound 50) and 7, 7-dimethyl-11- (3- {2- [1- (trifluoromethyl) cyclopropyl ]Ethoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.04, 8.09, 14]Docosac-1 (22), 9, 11, 13, 18, 20-hexaen-15, 17, 17-trione (enantiomer 2) (compound 51)

Step 1: 7, 7-dimethyl-11- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.04, 8.09, 14]Docosac-1 (22), 9, 11, 13, 18, 20-hexaen-15, 17, 17-trione (enantiomer 1) (compound 50) and 7, 7-dimethyl-11- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentanitrogenHeterotetracyclic [16.3.1.04, 8.09, 14]Docosac-1 (22), 9, 11, 13, 18, 20-hexaen-15, 17, 17-trione (enantiomer 2) (compound 51)

Racemic 7, 7-dimethyl-11- (3- {2- [1- (trifluoromethyl) cyclopropyl ] 11-methyl-2- [ was purified by SFC chromatography using ChiralPak AS-H (250 × 10mm column, 5 μm particle size) and 32% acetonitrile/methanol (90: 10; no modifier)/68% carbon dioxide mobile phase (10mL/min) (injection volume 70 μ L, 24mg/mL solution in acetonitrile/methanol (90: 10))]Ethoxy } -1H-pyrazol-1-yl) -17 lambda ⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.04, 8.09, 14]Didodec-1 (22), 9, 11, 13, 18, 20-hexaen-15, 17, 17-trione (26mg, 0.04246mmol) was subjected to chiral separation to give 7, 7-dimethyl-11- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid of the first enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.04, 8.09, 14]Docosal-1 (22), 9, 11, 13, 18, 20-hexaen-15, 17, 17-trione (enantiomer 1) (compound 50) (11.8mg, 92%); ESI-MS M/z calculated 605.2032, Experimental 606.3(M +1)⁺(ii) a Retention time: 1.93min (LC method B), and 7, 7-dimethyl-11- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid of the second enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.04, 8.09, 14]Docosal-1 (22), 9, 11, 13, 18, 20-hexaen-15, 17, 17-trione (enantiomer 2) (compound 51) (12.8 mg, 100%); ESI-MS M/z calculated 605.2032, Experimental 606.3(M +1)⁺(ii) a Retention time: 1.93min (LC method B).

Example 128: preparation of (14R) -8- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione(Compound 65)

Step 1: (14R) -8- [3- (3, 3-Dicyclopropylpropoxy) -1H-pyrazol-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 65)

Racemic 8- [3- (3, 3-Dicyclopropylpropoxy) -1H-pyrazol-1-yl was chromatographed by SFC using ChiralPak AS-H (250X 21.2mm column, 5 μm particle size) and a 38% acetonitrile: methanol (90: 10))/62% carbon dioxide mobile phase (70mL/min)]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Chiral separation of tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione to give (14R) -8- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl as the first enantiomer to be eluted, as a white solid]-12, 12-dimethyl-2 lambda ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 65) (51.2mg, 36%).¹H NMR (400MHz, chloroform-d) 10.10(s, 1H), 8.20(d, J ═ 2.8Hz, 1H), 8.06(d, J ═ 8.2Hz, 1H), 7.55(s, 1H), 7.50(d, J ═ 6.8Hz, 1H), 7.28(s, 1H), 6.57 (s, 1H), 5.91(d, J ═ 2.7Hz, 1H), 4.69(s, 1H), 4.43(t, J ═ 6.8Hz, 2H), 3.92(s, 1H), 3.34(t, J ═ 8.4Hz, 1H), 3.17(s, 1H), 3.06(s, 1H), 2.07(dd, J ═ 12.1, 7.5Hz, 1H), 1.97(q ═ 6.7, 7, 8, 7, 13, 7, 13, 7, 13, 7, 13, 7, 13, 7, 8, 13, 8, 13, 3.6Hz, 2H), 0.11(dp, J ═ 9.7, 4.7Hz, 2H). Calculated value of ESI-MS m/z619.29407, Experimental value 620.23(M +1)⁺(ii) a Retention time: 1.94min (LC method G).

Example 129: preparation of 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 21-pentaazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 67) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 21-pentaazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 68)

Step 1: 4- [4- [ [5- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] butyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

In a 20mL vial, 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (353.0mg, 0.9396mmol) and carbonyldiimidazole (152.4mg, 0.9396mmol) were combined in tetrahydrofuran (3.834mL) and stirred loosely at 50 ℃ for 120min, then 2, 2-dimethyl-4- [4- [ (5-sulfamoyl-2-pyridyl) amino group was added]Butyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (267.2mg, 0.6264 mmol) in tetrahydrofuran (5.114mL) followed by the addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (187.4 μ L, 1.253mmol) and the reaction was heated at 50 ℃ for 16h Gradient purifying to obtain white solid 4- [4- [ [5- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Butyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (422.4mg, 86%). ESI-MS M/z calculated 783.27924, Experimental 784.2(M +1)⁺(ii) a Retention time: 0.86min (LC method A).

Step 2: 2-chloro-N- [ [6- [4- (5, 5-dimethylpyrrolidin-3-yl) butylamino ] -3-pyridinyl ] sulfonyl ] -6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide

Reacting 4- [4- [ [5- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] group]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Butyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (422.4mg, 0.5386mmol) was dissolved in dichloromethane (1.843mL) and trifluoroacetic acid (1.904 mL, 24.71mmol) was added to the mixture and the mixture was stirred at room temperature for 60min. The organic layer was concentrated by rotary evaporation, followed by vacuum drying to give 2-chloro-N- [ [6- [4- (5, 5-dimethylpyrrolidin-3-yl) butylamino as an off-white solid ]-3-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (323.6mg, 88%). ESI-MS M/z calculated 683.2268, Experimental 684.2(M +1)⁺(ii) a Retention time: 0.58min (LC method A).

And step 3: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 21-pentaazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 67) and12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 21-pentaazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 68)

To 2-chloro-N- [ [6- [4- (5, 5-dimethylpyrrolidin-3-yl) butylamino]-3-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]To a solution of pyridine-3-carboxamide (323.6mg, 0.4730mmol) in dimethyl sulfoxide (12.94mL) were added potassium carbonate (392.2mg, 2.838 mmol), CsF (86.22mg, 0.5676mmol) and a small amount

And (3) a molecular sieve. The resulting mixture was capped and heated to 165 ℃ for 16h, then the mixture was cooled to room temperature, diluted with ethyl acetate and NH₄Saturated aqueous Cl and brine. The organic phase was dried (sodium sulfate), filtered and concentrated to 422mg of brown amorphous solid using a ChiralPak OD-3 column with an isocratic 30% methanol (20 mM NH) run over 2 minutes₃Chiral SFC chromatography of the brown amorphous solid on modifier)/70% carbon dioxide mobile phase elution yielded a single enantiomer of the desired product still containing some impurities (first elution, peak 1) and another single enantiomer of the desired product still containing some impurities (second elution, peak 2), both as white solids.

First eluted Peak 1(50.2mg) from SFC chiral separation was filtered and subjected to reverse phase HPLC-MS method with Luna C sold by Phenomenex₁₈(2) Column (75 × 30mM, 5 μm particle size) (pn: 00C-4252-U0-AX) and dual gradient run of 1% -99% mobile phase B over 15.0min (mobile phase a ═ water (5mM hydrochloric acid), mobile phase B ═ acetonitrile, flow rate 50mL/min, injection volume 950 μ L and column temperature 25 ℃) purification to give 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) ring) as a white solid Propyl radical]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 21-pentaazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 67) (27.7mg, 18%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.15(s, 1H), 8.47(s, 1H), 8.19(d, J ═ 2.7Hz, 1H), 7.81(d, J ═ 8.3Hz, 1H), 7.30(s, 1H), 6.89(d, J ═ 8.3Hz, 1H), 6.56(d, J ═ 8.9Hz, 1H), 6.10(d, J ═ 2.7Hz, 1H), 4.31(t, J ═ 7.0Hz, 2H), 2.45(s, 1H), 2.07(t, J ═ 7.1Hz, 3H), 1.99(s, 1H), 1.72(s, 1H), 1.54(s, 10H), 1.25(d, J ═ 9.7Hz, 2H), 1.05 (s, 2H), 0.92 (s, 0.92, 0.84H), 0.84 (m-0H). ESI-MS M/z calculated 647.2502, Experimental 648.2(M +1)⁺(ii) a Retention time: 2.12min (LC method B).

The second eluted peak 2(46.5mg) from the SFC chiral separation was filtered and subjected to the reverse phase HPLC-MS method using Luna C sold by Phenomenex₁₈(2) Column (75 × 30mM, 5 μm particle size) (pn: 00C-4252-U0-AX) and dual gradient run of 1% -99% mobile phase B over 15.0min (mobile phase a ═ water (5mM hydrochloric acid), mobile phase B ═ acetonitrile, flow rate 50mL/min, injection volume 950 μ L and column temperature 25 ℃) purification to give 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] 8 as a white solid ]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 21-pentaazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 68) (29.4mg, 19%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.15(s, 1H), 8.46(s, 1H), 8.19(d, J ═ 2.8Hz, 1H), 7.80(d, J ═ 8.5Hz, 1H), 7.28(s, 1H), 6.88(d, J ═ 8.3Hz, 1H), 6.55(d, J ═ 8.9Hz, 1H), 6.10(d, J ═ 2.7Hz, 1H), 4.31(t, J ═ 7.0Hz, 2H), 2.07(t, J ═ 7.1Hz, 3H), 1.99(s, 1H), 1.72(d, J ═ 10.9Hz, 1H), 1.54(d, J ═ 1.3Hz, 10H), 1.29-1.14(m, 2H), 1.04(s, 2H), 97.91 (s, 0.91, 0.86-0H), 0.86(m, 2H). ESI-MS M/z calculated 647.2502, Experimental 648.2(M +1)⁺(ii) a Retention time: 2.11min (LC method B).

Example 130: preparation of 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (22), 5(10), 6, 8, 19(23), 20-hexaen-2, 2, 4-trione (compound 69)

Step 1: 4- [2- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] ethoxy ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (154mg, 0.4099mmol) and carbonyldiimidazole (66mg, 0.4070mmol) were combined in tetrahydrofuran (2.0mL) and stirred at 50 ℃ for 90min, then 2, 2-dimethyl-4- [2- [ (6-sulfamoyl-2-pyridyl) amino]Ethoxy radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (94mg, 0.2268mmol) was added followed by 1, 8-diazabicyclo [5.4.0]Undec-7-ene (85.0 μ L, 0.5684mmol) and the reaction was heated at 50 ℃ for 36h. The organics were separated, dried over sodium sulfate, filtered and evaporated, and then chromatographed by reverse phase preparative chromatography using C₁₈Purifying with column (30% -99% acetonitrile/water (5mM hydrochloric acid)) to obtain 4- [2- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] methyl ] ethyl ] phenyl ] ethyl ] propyl ] hydrate as white solid]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Ethoxy radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (77mg, 44%). ESI-MS M/z calculated 771.24286, Experimental 772.2(M +1)⁺(ii) a Retention time: 2.28min (LC method E).

Step 2: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester ]Ethoxy } -1H-pyrazol-1-yl) -15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (22), 5(10), 6, 8, 19(23), 20-hexaen-2, 2, 4-trione (compound 69)

Reacting 4- [2- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] group]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Ethoxy radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (77mg, 0.09971mmol) was dissolved in dichloromethane (1.6mL) and to the mixture was added hydrochloric acid (800 μ L, 4M in dioxane, 3.200mmol) and the mixture was stirred at room temperature for 30min

Molecular sieves and dimethylsulfoxide (1.6mL) were combined in a vial, purged with nitrogen, capped, heated to 150 ℃, and stirred for 20h ₁₈Column (30% -99% acetonitrile/water (5mM hydrochloric acid)) to give 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Ethoxy } -1H-pyrazol-1-yl) -15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5(10), 6, 8, 19(23), 20-hexaen-2, 2, 4-trione (compound 69) (38.8mg, 61%).¹H NMR (400MHz, dimethylsulfoxide-d)₆) 12.59(s，1H)，8.20(d，J＝2.8Hz，1H)，7.80(d，J＝8.2Hz，1H)，7.59(dd，J＝8.5，7.3 Hz，1H)，7.13(d，J＝7.7Hz，1H)，7.10(d，J＝7.0Hz，1H)，6.94(d，J＝8.2Hz，1H)， 6.71(d，J＝8.2Hz，1H) 6.11(d, J ═ 2.7Hz, 1H), 4.31(t, J ═ 7.0Hz, 2H), 4.11(td, J ═ 12.8, 5.9Hz, 2H), 3.88(t, J ═ 11.6Hz, 1H), 3.61(dd, J ═ 8.7, 4.2Hz, 1H), 3.32-3.20 (m, 1H), 3.06(dd, J ═ 10.6, 5.0Hz, 1H), 2.92-2.77(m, 1H), 2.08(t, J ═ 7.1Hz, 3H), 1.79(t, J ═ 10.9Hz, 1H), 1.57(d, J ═ 9.8Hz, 6H), 1.00-0.93(m, 2H), 0.88(s, 2H). ESI-MS M/z calculated 635.21375, Experimental 636.2(M +1)⁺(ii) a Retention time: 2.0min (LC method E).

Example 131: preparation of 21, 21, 23-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaen-8, 10, 10-trione (compound 76) and 12, 21, 21-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaene-8, 10, 10-trione (compound 71)

Step 1: 4- [4- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -3-methyl-pyrazol-1-yl ] butyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 4- [4- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -5-methyl-pyrazol-1-yl ] butyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (mixture of regioisomers)

Adding 2-chloro-N- [ (5-methyl-1H-pyrazol-4-yl) sulfonyl group to a vial]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (454mg, 0.8749mmol), N-dimethylformamide (4mL) and carbonPotassium (424mg, 3.068mmol) the reaction was stirred at room temperature for 5min and then N, N-dimethylformamide (2mL) containing tert-butyl 2, 2-dimethyl-4- (4-methylsulfonyloxybutyl) pyrrolidine-1-carboxylate (410mg, 1.173mmol) was added dropwise the reaction was placed in an 80 ℃ oil bath overnight the reaction was cooled to room temperature filtered and purified by HPLC (10% -99% acetonitrile: water + 0.1% hydrochloric acid modifier) to give 4- [4- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] amine ]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-3-methyl-pyrazol-1-yl]Butyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 4- [4- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-5-methyl-pyrazol-1-yl]Butyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (mixture of regioisomers) (184.3mg, 27%). ESI-MS calc/z 771.27924, experimental 772.7(M +1)⁺(ii) a Retention time: 1.85min (LC method G).

Step 2: 2-chloro-N- [1- [4- (5, 5-dimethylpyrrolidin-3-yl) butyl ] -3-methyl-pyrazol-4-yl ] sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide and 2-chloro-N- [1- [4- (5, 5-dimethylpyrrolidin-3-yl) butyl ] -5-methyl-pyrazol-4-yl ] sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide (mixture of regioisomers).

Adding 4- [4- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] to the flask]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-3-methyl-pyrazol-1-yl]Butyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 4- [4- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] methyl ester ]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-5-methyl-pyrazol-1-yl]Butyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (mixture of regioisomers) (81mg, 0.1049mmol), dichloromethane (3mL) and trifluoroacetic acid (450 μ L, 5.841 mmol). The reaction was stirred at room temperature for 90min, evaporated, washed with 2M potassium carbonateThe residue was washed and extracted with ethyl acetate the organic layer was dried over sodium sulfate, filtered and evaporated to give 2-chloro-N- [1- [4- (5, 5-dimethylpyrrolidin-3-yl) butyl]-3-methyl-pyrazol-4-yl]Sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide and 2-chloro-N- [1- [4- (5, 5-dimethylpyrrolidin-3-yl) butyl]-5-methyl-pyrazol-4-yl]Sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (mixture of regioisomers) (70mg, 99%). ESI-MS M/z calculated 671.2268, Experimental 672.2(M +1)⁺(ii) a Retention time: 1.64min (LC method B).

And step 3: 21, 21, 23-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [17.2.1.111, 14.02, 7 ]Tricosano-2, 4, 6, 11(23), 12-pentaen-8, 10, 10-trione (compound 76) and 12, 21, 21-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaene-8, 10, 10-trione (compound 71)

To 2-chloro-N- [1- [4- (5, 5-dimethylpyrrolidin-3-yl) butyl]-3-methyl-pyrazol-4-yl]Sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide and 2-chloro-N- [1- [4- (5, 5-dimethylpyrrolidin-3-yl) butyl]-5-methyl-pyrazol-4-yl]Sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]To pyridine-3-carboxamide (mixture of regioisomers) (70mg, 0.1041mmol) was added potassium carbonate (72mg, 0.5210mmol), cesium fluoride (36mg, 0.2370mmol) and dimethyl sulfoxide (800 μ L.) the reaction was heated at 150 ℃ overnight. The reaction was cooled to room temperature, filtered and purified by HPLC (20% -80% acetonitrile/water + 0.1% hydrochloric acid modifier) to give 12, 21, 21-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as the first peak to eluteBase of]Ethoxy } -1H-pyrazol-1-yl) -10 lambda ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaen-8, 10, 10-trione (compound 71) (16.6mg, 50%);¹h NMR (400MHz, dimethylsulfoxide-d)₆) 12.25(s, 1H), 8.63(s, 1H), 8.21(dd, J ═ 4.5, 2.8Hz, 1H), 7.85-7.74(M, 1H), 6.92 (dd, J ═ 8.3, 4.4Hz, 1H), 6.11(dd, J ═ 2.7, 1.5Hz, 1H), 4.31(q, J ═ 6.4, 5.9Hz, 3H), 4.10(dd, J ═ 11.9, 6.8Hz, 1H), 2.85(t, J ═ 10.1Hz, 1H), 2.67(bs, 1H), 2.39(s, 3H), 2.15-2.02(M, 4H), 1.83 (ESI, J ═ 11.8, 5.6, 1H), 1.58 (s, 3H), 2.15-2.02(M, 4H), 1.83 (ESI, J ═ 11.8, 5.6, 1H), 1H, 7 (J ═ 0, 7.84 (z, 1H), 2.3H, 3H), 2.83 (M, 3H), 3H), 13 (M, 3H), 13 (d, 3H), 13 (H, 3H, M, 3H), 13, 3H), 3H, M, 3H, 2.83 (H), 2.3H, M.⁺(ii) a Retention time: 2.14 min (LC method B) and 21, 21, 23-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as the second peak to elute]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaen-8, 10, 10-trione (compound 76) (4.2 mg, 13%); ESI-MS M/z calculated 635.2502, Experimental 636.3(M +1) ⁺(ii) a Retention time: 2.08 min (LC method B)

Example 132: preparation of 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5(10), 6, 8, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 1) (compound 74) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5(10), 6, 8, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 2) (compound 75)

Step 1: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5(10), 6, 8, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 1) (compound 74) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosan-1 (22), 5(10), 6, 8, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 2) (compound 75)

Chromatography by SFC using ChiralPak AS-H (250X 21.2mM column, 5 μm particle size) and 5% to 60% methanol (20mM NH)₃) Gradient of/carbon dioxide mobile phase (50mL/min) vs. racemic 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ] -alpha-methyl-2-methyl-ethyl- ] -alpha-methyl-]Ethoxy } -1H-pyrazol-1-yl) -15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]The tetracosan-1 (22), 5(10), 6, 8, 19(23), 20-hexaen-2, 2, 4-trione (36mg, 0.05607mmol) was subjected to chiral separation to give 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] ketone as the first enantiomer to be eluted as an off-white solid]Ethoxy } -1H-pyrazol-1-yl) -15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5(10), 6, 8, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 1) (compound 74) (9.76mg, 54%); ESI-MS M/z calculated 635.21375, Experimental 636.2(M +1)⁺(ii) a Retention time: 2.0min (LC method E), and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as an off-white solid as the second enantiomer to be eluted ]Ethoxy } -1H-pyrazol-1-yl) -15-oxa-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5(10), 6, 8, 19 (23)) 20-hexaen-2, 2, 4-trione (enantiomer 2) (compound 75) (11.29mg, 63%); ESI-MS M/z calculated 635.21375, Experimental 636.2(M +1)⁺(ii) a Retention time: 2.0min (LC method E).

Example 133: preparation of 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 23-tetraazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 78)

Step 1: 2, 2-dimethyl-4- [4- (6-sulfamoyl-2-pyridyl) but-3-ynyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

6-bromopyridine-2-sulfonamide (840mg, 3.543mmol), trans-dichlorobis (triphenylphosphine) palladium (II) (125mg, 0.1781mmol), and cuprous iodide (34mg, 0.1785mmol) were added in that order in a round bottom flask. Subsequently, anhydrous N, N-dimethylformamide (11mL) was added to the vessel, which was sealed with a rubber septum under nitrogen, followed by the addition of diisopropylamine (1000. mu.L, 7.135 mmol). Subsequently, 3mL of N, N-dimethylformamide containing 4-but-3-ynyl-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.15g, 4.575mmol) were added and the reaction mixture was heated to 100 ℃ in an oil bath under a nitrogen atmosphere for 2 h. The residue was diluted with ethyl acetate and washed with water (2 × 50mL), followed by brine (50 mL). The organic layers were combined, dried (sodium sulfate), filtered and concentrated to an orange residue which was purified by silica gel chromatography using a gradient of 100% hexane to 90% ethyl acetate/hexane to give 2, 2-dimethyl-4- [4- (6-sulfamoyl-2-pyridyl) but-3-ynyl as a pale yellow foam ]Pyrrolidine-1-carboxylic acid tert-butyl ester (1.4g, 97%).¹H NMR (400 MHz, dimethylsulfoxide-d)₆)8.04(t，J＝7.8Hz，1H)，785(dd, J ═ 7.9, 0.8Hz, 1H), 7.67 (dd, J ═ 7.7, 3.5Hz, 1H), 7.53(s, 2H), 3.63(dd, J ═ 18.0, 9.0Hz, 1H), 2.88(q, J ═ 10.5Hz, 1H), 2.58-2.52(M, 1H), 2.24(s, 1H), 1.94(dd, J ═ 20.1, 6.4Hz, 1H), 1.64 (dd, J ═ 14.1, 7.0Hz, 2H), 1.50(dd, J ═ 22.0, 9.7Hz, 1H), 1.39(dd, J ═ 18.3, 9.6, 13H), 1.26(s, 3H), 3-25M, 25M/z + M (calculated value of M + 408 Hz, 1H)⁺(ii) a Retention time: 1.77min (LC method E).

Step 2: 2, 2-dimethyl-4- [4- (6-sulfamoyl-2-pyridyl) butyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

To 2, 2-dimethyl-4- [4- (6-sulfamoyl-2-pyridyl) but-3-ynyl]Pyrrolidine-1-carboxylic acid tert-butyl ester (1.1g, 2.699mmol) to which platinum oxide (61.29mg, 0.2699mmol) was added, followed by methanol (11.00 mL), and the mixture was purged with nitrogen, followed by hydrogen, followed by a balloon closure with hydrogen, and stirred for 4h. The residue was then purified by silica gel chromatography using a gradient of 100% hexane to 100% ethyl acetate to give 2, 2-dimethyl-4- [4- (6-sulfamoyl-2-pyridyl) butyl ] as a yellow foam ]Pyrrolidine-1-carboxylic acid tert-butyl ester (1.10g, 99%) which was mixed with a small amount of olefinic intermediate and used directly in the next step ESI-MS calculated M/z 411.21918, experimental 412.2(M +1)⁺(ii) a Retention time: 1.85min (LC method E).

And step 3: 4- [4- [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] butyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro is reacted with-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (685mg, 1.823mmol) and carbonyldiimidazole (296mg, 1.825mmol) were combined in tetrahydrofuran (11mL) and stirred at 50 ℃ for 90min, then 2, 2-dimethyl-4- [4- (6-sulfamoyl-2-pyridyl) butyl ] was added]Pyrrolidine-1-carboxylic acid tert-butyl ester (500mg, 1.215mmol) followed by addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (455. mu.L, 3.043mmol) and the reaction was heated at 50 ℃ for 18 h. The organics were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexane to 75% ethyl acetate/hexane to give 4- [4- [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] hexane as an off-white solid ]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Butyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (165mg, 35%). ESI-MS M/z calculated 768.2684, experimental 769.2(M +1)⁺(ii) a Retention time: 2.13min (LC method G).

And 4, step 4: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 23-tetraazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 78)

4- [4- [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Butyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (125mg, 0.1625 mmol) was dissolved in dichloromethane (2.5mL) and hydrochloric acid (1.5mL, 4M in dioxane, 6.000mmol) was added to the mixture and stirred at room temperature for 30 min. The mixture was concentrated to dryness under reduced pressure, and reacted with potassium carbonate (135mg, 0.9768mmol), cesium fluoride (40mg, 0.2633mmol),

Molecular sieves and dimethylsulfoxide (2.5mL) were combined in a vial, purged with nitrogen, capped, heated to 150 ℃, and stirred for 20h ₁₈Column (30% -99% acetonitrile/water (5mM hydrochloric acid)) to give 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 23-tetraazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 78) (37.67mg, 37%). ESI-MS M/z calculated 632.23926, Experimental 633.2(M +1)⁺(ii) a Retention time: 1.92min (LC method G).

Example 134: preparation of 21, 21, 23-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaen-8, 10, 10-trione (enantiomer 1) (compound 80) and 21, 21, 23-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 81)

Step 1: 21, 21, 23-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaen-8, 10, 10-trione (enantiomer 1) (compound 80) and 21, 21, 23-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 81)

Chromatography by SFC using ChiralPak AS-H (250X 21mM column, 5 μm particle size) and 20% -25% methanol (20mM NH)₃) Carbon dioxide mobile phase (50mL/min) (950 μ L injection volume, 4 mg/mL solution in 50% methanol in dimethylsulfoxide) pair 21, 21, 23-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [17.2.1.111, 14.02, 7]Ditridec-2, 4, 6, 11(23), 12-pentaen-8, 10, 10-trione (12mg, 0.01888 mmol) was subjected to chiral separation to give 21, 21, 23-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl-4 ] as the first enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -10 lambda ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaen-8, 10, 10-trione (enantiomer 1) (compound 80) (3.3mg, 55%); ESI-MS M/z calculated 635.2502, Experimental 636.3(M +1)⁺(ii) a Retention time: 2.95min (LC method D) and 21, 21, 23-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as the second enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaen-8, 10, 10-trione (enantiomer 2) (compound 81) (3.8mg, 63%); ESI-MS M/z calculated 635.2502, Experimental 636.3(M +1)⁺(ii) a Retention time: 2.95min (LC method D).

Example 135: preparation of 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 23-tetraazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 86) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda ⁶-thia-3, 9, 11, 23-tetraazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaEne-2, 2, 4-trione (enantiomer 2) (compound 87)

Step 1: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 23-tetraazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 86) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 23-tetraazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 87)

Chromatography by SFC using Chiral Pak AS-H (250X 10mm), column, 5 μm particle size) and 25% acetonitrile/methanol (90: 10; no modifier), 75% carbon dioxide mobile phase (10mL/min) (infusion volume 70 μ L, about 24mg/mL in acetonitrile: methanol (90: 10) to racemic 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl)]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 23-tetraazatetracyclo [17.3.1.111, 14.05, 10 ]The tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (34.9mg, 0.05516 mmol) was subjected to chiral separation to give 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] ketone as the first enantiomer to be eluted as a white solid]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 23-tetraazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 86) (13.11mg, 74%);¹h NMR (400MHz, dimethylsulfoxide-d)₆)12.74 (s，1H)，8.21(d，J＝2.7Hz，1H)，8.08(t，J＝7.7Hz，1H)，8.01(d，J＝7.6Hz，1H)， 7.78(d，J＝7.6Hz, 1H), 7.64(d, J ═ 7.6Hz, 1H), 6.92(d, J ═ 8.2Hz, 1H), 6.12(d, J ═ 2.7Hz, 1H), 4.32(t, J ═ 7.0Hz, 2H), 2.87(s, 2H), 2.84-2.77(M, 1H), 2.67(t, J ═ 12.6Hz, 1H), 2.16(dd, J ═ 11.5, 5.3Hz, 1H), 2.08(t, J ═ 7.0Hz, 2H), 1.98-1.85(M, 2H), 1.61(s, 1H), 1.53(t, J ═ 24.3Hz, 8H), 1.45(s, 1H), 1.03(dd, J ═ 12, 9, 7.8H), 7.8 (s, 1H), 7.8 (M, 7, 7.8H), 7, 7.8 (z ═ 2H), 1H, 5 (d, 7, 8H), 1H), 5 (z, 2H), 2H, 7, 2H), 5 (d, 2H), 3, 7, 2H), 3, 2H), 3, 7, 1⁺(ii) a Retention time: 1.88min (LC method G) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid of the second enantiomer to be eluted ]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 23-tetraazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 87) (12.96mg, 74%); ESI-MS M/z calculated 632.23926, Experimental 633.2(M +1)⁺(ii) a Retention time: 1.92min (LC method G).

Example 136: preparation of 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -18-oxa-2. lambda⁶-thia-3, 9, 11, 20-tetraazatetracyclo [17.2.2.111, 14.05, 10]Tetracosane-1 (21), 5(10), 6, 8, 19, 22-hexaen-2, 2, 4-trione (compound 90)

Step 1: 2, 2-dimethyl-4- [3- [ (5-sulfamoyl-2-pyridyl) oxy ] propyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred N, N-dimethylformamide (4.0mL) containing tert-butyl 4- (3-hydroxypropyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (400mg, 1.554mmol) under a nitrogen atmosphere was added NaH (125mg, 3.125mmol) portionwise (note: gas evolution), andthe mixture was stirred at room temperature for 20 min. 6-chloropyridine-3-sulfonamide (296mg, 1.537mmol) was then added and the resulting mixture was stirred at room temperature for 140min, followed by NaH (62mg, 1.550mmol) (note: gas evolution) and after equipping the reflux condenser the resulting mixture was heated to 100 ℃ for 20h. More 6-chloropyridine-3-sulfonamide (145mg, 0.750mmol), NaH (62mg, 1.55mmol) was added and heated to 105 ℃ for 20h, then the mixture was poured into 1N citric acid and extracted with ethyl acetate (2 ×). The organic fractions were combined, dried (sodium sulfate), filtered and concentrated to a yellow oil which was purified by silica gel chromatography using a gradient of 100% hexane to 65% ethyl acetate/hexane to give 2, 2-dimethyl-4- [3- [ (5-sulfamoyl-2-pyridyl) oxy ] hexane ]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (50.36mg, 8%). ESI-MS M/z calculated 413.19846, Experimental value 414.2(M +1)⁺(ii) a Retention time: 1.81min (LC method E).

Step 2: 4- [3- [ [5- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] oxy ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (69mg, 0.1836mmol) and carbonyldiimidazole (30mg, 0.1850mmol) were combined in tetrahydrofuran (1.108mL) and stirred at room temperature for 90min, then 2, 2-dimethyl-4- [3- [ (5-sulfamoyl-2-pyridyl) oxy]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (50.36mg, 0.1218mmol) was added followed by 1, 8-diazabicyclo [5.4.0]Undec-7-ene (50 μ L, 0.3343mmol) and the reaction was heated at 50 ℃ for 18h. The organics were separated, dried over sodium sulfate, filtered and evaporated, then purified by silica gel chromatography using a gradient of 100% hexane to 75% ethyl acetate/hexane to give 4- [3- [ [5- [ [ 2-chloro-6- [3- [2- [1- (tris-2-chloro-6- [3 ] hexane as an off-white solid Fluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Oxy radical]Propyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (71mg, 76%). ESI-MS M/z calculated 770.2476, Experimental 771.2 (M +1)⁺(ii) a Retention time: 2.11min (LC method E).

And step 3: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -18-oxa-2. lambda⁶-thia-3, 9, 11, 20-tetraazatetracyclo [17.2.2.111, 14.05, 10]Tetracosane-1 (21), 5(10), 6, 8, 19, 22-hexaen-2, 2, 4-trione (compound 90)

Reacting 4- [3- [ [5- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] group]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Oxy radical]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (71mg, 0.09206mmol) was dissolved in dichloromethane (1.5mL) and hydrochloric acid (4M in dioxane) (800 μ L, 4M, 3.200mmol) was added to the mixture and the mixture was stirred at room temperature for 30 min. The mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate, and then 2M aqueous sodium carbonate (5mL) was added to bring the pH to about 10. The organic layer was extracted with ethyl acetate (2X 10mL), washed with brine, then dried over sodium sulfate, filtered, and evaporated to dryness under reduced pressure the resulting material was combined with potassium carbonate (69mg, 0.4993mmol), cesium fluoride (23mg, 0.1514mmol),

Molecular sieves and dimethylsulfoxide (1.5mL) were combined in a vial, purged with nitrogen, capped, heated to 155 ℃, and stirred for 24 h. Cooling to room temperature, filtering, and then performing reverse-phase preparative chromatography using C₁₈Column (30% -99% acetonitrile/water (5mM hydrochloric acid)) to give 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as an off-white solid]Ethoxy } -1H-pyrazol-1-yl) -18-oxa-2. lambda⁶-thia-3, 9, 11, 20-tetraazatetracyclo [17.2.2.111, 14.05, 10]Twenty four carbon-1(21), 5(10), 6, 8, 19, 22-hexaen-2, 2, 4-trione (compound 90) (3.95mg, 7%). ESI-MS M/z calcd 634.2185, Experimental 635.2(M +1)⁺(ii) a Retention time: 2.27min (LC method E).

Example 137: preparation of 12, 21, 21-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaen-8, 10, 10-trione (enantiomer 1) (compound 91) and 12, 21, 21-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [17.2.1.111, 14.02, 7 ]Tricosano-2, 4, 6, 11(23), 12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 92)

Step 1: 12, 21, 21-trimethyl-1- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaen-8, 10, 10-trione (enantiomer 1) (compound 91) and 12, 21, 21-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 92)

By SFC chromatography using Chiral Pak AS-H (250X 10mM), column, 5 μm particle size) and 20% -30% methanol (20mM NH)₃) Carbon dioxide flow vs. rac 12, 21, 21-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosane-2, 4, 6, 11(23), 12-pentaene-8, 10, 10-trione (35mg, 0.05506mmol) was subjected to chiral separation to give 12 as the first enantiomer to be eluted, 21, 21-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaen-8, 10, 10-trione (enantiomer 1) (compound 91) (12.1mg, 69%); ESI-MS M/z calculated 635.2502, Experimental 636.3(M +1)⁺(ii) a Retention time: 3.04min (LC method G) and 12, 21, 21-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as the second enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 92) (8.9mg, 51%); ESI-MS M/z calculated 635.2502, Experimental 636.3(M +1)⁺(ii) a Retention time: 3.03min (LC method G).

Example 138: preparation of 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 20-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 93)

Step 1: 2, 2-dimethyl-4- [3- [ (4-sulfamoyl-2-pyridyl) amino ] propyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloropyridine-4-sulfonamide (300mg, 1.557mmol), tert-butyl 4- (3-aminopropyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (399.2mg, 1.557mmol), sodium tert-butoxide (224.4 mg, 2.335mmol), and chlorine (2-di-tert-butylphosphino-2 ', 4', 6 '-triisopropyl-1, 1' -biphenyl) [2- (2-aminoethyl) phenyl ] were purged with nitrogen]A solution of palladium (II) (202.8mg, 0.3114mmol) in dioxane (5.000mL) was degassed and stirred at room temperatureThe mixture was stirred for 2 h. The reaction mixture was diluted with ethyl acetate and washed with brine solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated the resulting brown residue was purified by silica gel column chromatography using a gradient of 100% dichloromethane to 20% methanol/dichloromethane to give 2, 2-dimethyl-4- [3- [ (4-sulfamoyl-2-pyridyl) amino as a light brown viscous solid]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (175mg, 27% with 4- [3- [ bis (4-sulfamoyl-2-pyridyl) amino]Propyl radical]ESI-MS calcd for M/z 412.21442, experimental value 413.6(M +1)⁺(ii) a Retention time: 0.5min (LC method A).

Step 2: 4- [3- [ [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (154.8 mg, 0.4120mmol) and carbonyldiimidazole (66.81mg, 0.4120mmol) were combined in tetrahydrofuran (2.0mL) and stirred at 50 ℃ for 90min, then 2, 2-dimethyl-4- [3- [ (4-sulfamoyl-2-pyridyl) amino]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (85mg, 0.2060mmol) was added followed by 1, 8-diazabicyclo [5.4.0]Undec-7-ene (47.04mg, 46.21. mu.L, 0.3090mmol) and the reaction was heated at 50 ℃ for 18 h. The reaction was diluted with ethyl acetate and washed with a saturated solution of ammonium chloride followed by brine the organics were separated, dried over sodium sulfate, filtered and evaporated. The resulting brown residue was purified by reverse phase HPLC-MS method using a dual gradient run of 20% -99% mobile phase B over 15.0min (mobile phase a ═ water (5mM hydrochloric acid), mobile phase B ═ acetonitrile, flow rate ═ 50mL/min, injection volume ═ 950 μ L and column temperature ═ 25 ℃) to give 4- [3- [ [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] propyl ] as an off-white solid]Ethoxy radical]Pyrazol-1-yl]Pyridine compound-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (45.6mg, 29%). ¹H NMR (400MHz, chloroform-d) 8.33 to 8.28(m, 1H), 8.28 to 8.12(m, 2H), 7.70(dd, J ═ 8.2, 4.3Hz, 1H), 7.28(d, J ═ 6.1Hz, 1H), 7.21(d, J ═ 16.4Hz, 1H), 5.95(t, J ═ 2.7Hz, 1H), 4.39(t, J ═ 7.1Hz, 2H), 3.77 to 3.68(m, 1H), 3.68 to 3.52(m, 1H), 3.38(s, 2H), 2.85(t, J ═ 11.7Hz, 1H), 2.23 to 2.11(m, 1H), 2.09 (t, J ═ 7.2, 2H), 1.94 (m, 1H), 1.79(m, 1H), 2.73 (m, 2H), 2.73 (m, 1H), 2H). ESI-MS M/z calculated 769.2636, Experimental 770.4(M +1)⁺(ii) a Retention time: 0.77min (LC method A).

And step 3: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 20-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 93)

4- [3- [ [4- [ [ 2-amino-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] at room temperature]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]A solution of tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (50 mg, 0.06491mmol) in dichloromethane (416.7 μ L) and trifluoroacetic acid (74.01mL, 49.67 μ L, 0.6491 mmol) was stirred for 4h. The resulting residue was dissolved in dimethyl sulfoxide (2.500mL) and added

Molecular sieves and stir the reaction mixture for 10 min. Subsequently, cesium fluoride (29.58mg, 0.1947mmol) and potassium carbonate (26.91mg, 0.1947mmol) were added and the reaction mixture was heated at 130 ℃ overnight(puradisc 25 TF) the reaction mixture was filtered and the filtrate was purified by reverse phase HPLC-MS method using a double gradient run of 20% -80% mobile phase B over 15.0min (mobile phase a ═ water (0.05% hydrochloric acid), mobile phase B ═ acetonitrile) to give 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a pale yellow solid]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 20-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 93) (12.3mg, 30%).¹H NMR (400 MHz, chloroform-d) 8.39-8.22(M, 1H), 8.16(s, 1H), 7.94(s, 2H), 7.61(s, 1H), 7.20(s, 1H), 6.98(s, 1H), 5.91(s, 1H), 4.37(s, 2H), 3.47(d, J ═ 13.7Hz, 2H), 3.01(d, J ═ 43.7Hz, 2H), 2.20(s, 1H), 2.08(t, J ═ 7.1Hz, 3H), 1.86(s, 2H), 1.71(s, 2H), 1.65(s, 3H), 1.61(s, 3H), 1.30(d, J ═ 39.7Hz, 2H), 1.05-0.98(M, 2H), 0.74(s, 3H), 0.7 (s, 3H), 1.7H), experimental calculated values of M + esim + 25M + z) ⁺(ii) a Retention time: 1.75min (LC method B).

Example 139: preparation of 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda⁶-thia-3, 9, 11, 21-tetraazatetracyclo [18.2.2.111, 14.05, 10]Pentacosane-1 (23), 5, 7, 9, 20(24), 21-hexaene-2, 2, 4-trione (compound 94)

Step 1: 2, 2-dimethyl-4- [4- [ (5-sulfamoyl-2-pyridyl) oxy ] butyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred N, N-dimethylformamide (8mL) containing tert-butyl 4- (4-hydroxybutyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (800mg, 2.948mmol) under a nitrogen atmosphere was added NaH (240mg, 6.001mmol) portionwise in a 20mL vial (note: gasPrecipitated) and the mixture was stirred at room temperature for 20min then 6-chloropyridine-3-sulfonamide (570mg, 2.959mmol) was added and the resulting mixture was stirred at room temperature for 1h followed by the addition of NaH (120mg, 3.000mmol) (note: gas evolution), the vial was capped and the resulting mixture was heated to 100 ℃ for 20 h. 6-chloropyridine-3-sulfonamide (145mg, 0.750mmol) and NaH (62mg, 1.55mmol) were additionally added and heated to 105 ℃ for 48 h. The mixture was then poured into 1N citric acid and extracted with ethyl acetate (2 ×) the organic fractions were combined, dried (sodium sulfate), filtered and concentrated to a yellow oil which was purified by silica gel chromatography using a gradient of 100% hexane to 65% ethyl acetate/hexane followed by a second silica gel purification using a gradient of 100% dichloromethane to 15% methanol/dichloromethane to give 2, 2-dimethyl-4- [4- [ (5-sulfamoyl-2-pyridyl) oxy as a clear viscous oil ]Butyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (335mg, 27%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)8.54(d, J ═ 2.1Hz, 1H), 8.10-7.95(M, 1H), 7.44(d, J ═ 6.2Hz, 2H), 6.98(d, J ═ 8.8Hz, 1H), 4.32(t, J ═ 6.6Hz, 2H), 3.55(dd, J ═ 17.1, 6.9Hz, 1H), 2.78(q, J ═ 10.5Hz, 1H), 2.19-2.01(M, 1H), 1.95-1.80(M, 1H), 1.76-1.68(M, 2H), 1.44(d, J ═ 12.1Hz, 2H), 1.40-1.36(M, 12H), 1.32(d, J ═ 17.3Hz, 3H), 1.24(s, 3H), 25.428 (M, 1H), calculated values of experiment/M + 428)⁺(ii) a Retention time: 1.87min (LC method E).

Step 2: 4- [4- [ [5- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] oxy ] butyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (437.0 mg, 1.163mmol) and carbonyldiimidazole (190.0mg, 1.172mmol) were combined in tetrahydrofuran (7.260mL) and stirred at 50 ℃ for 90min, then, 2 was added,2-dimethyl-4- [4- [ (5-sulfamoyl-2-pyridyl) oxy]Butyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (330mg, 0.7718mmol) was added followed by 1, 8-diazabicyclo [5.4.0 ]Undec-7-ene (322.6mg, 316.9 μ L, 2.119mmol) and the reaction was heated at 50 ℃ for 20 h. The reaction was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate followed by brine. The organics were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexane to 55% ethyl acetate/hexane followed by a second silica gel purification using a gradient of 100% dichloromethane to 15% methanol/dichloromethane to give 4- [4- [ [5- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] propyl ] as a pale yellow solid]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Oxy radical]Butyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (350mg, 58%). ESI-MS M/z calculated 784.2633, Experimental 785.2(M +1)⁺(ii) a Retention time: 2.19min (LC method G).

And step 3: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda⁶-thia-3, 9, 11, 21-tetraazatetracyclo [18.2.2.111, 14.05, 10]Pentacosane-1 (23), 5, 7, 9, 20(24), 21-hexaene-2, 2, 4-trione (compound 94)

Reacting 4- [4- [ [5- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] group ]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Oxy radical]Butyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (350mg, 0.4457mmol) was dissolved in dichloromethane (7.5mL) and to this mixture was added hydrochloric acid (4.0mL, 4M in dioxane, 16.00mmol) and stirred at room temperature for 30min the mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate and then added 2M aqueous sodium carbonate (5mL) to a pH of about 10, extracted with ethyl acetate (2 x 10mL), the organic layers were combined, washed with brine, then dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure the resulting material and potassium carbonate (310mg,2.243mmol), cesium fluoride (105mg, 0.6912mmol),

Molecular sieves and dimethylsulfoxide (7.5mL) were combined in a vial, purged with nitrogen, capped, heated to 150 ℃, and stirred for 20 h. Cooling to room temperature, and filtering the mixture, diluting with ethyl acetate and washing with a saturated aqueous solution of sodium bicarbonate, followed by brine the organics were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexane to 55% ethyl acetate/hexane to give 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] hexane as an off-white solid ]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda⁶-thia-3, 9, 11, 21-tetraazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (compound 94) (76.3mg, 26%). ESI-MS M/z Calculation 648.2342, Experimental value 649.2(M +1)⁺(ii) a Retention time: 2.41min (LC method E).

Example 140: preparation of (14S) -8- [3- (3, 3-dimethylbutyl) -4-methyl-2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (hydrochloride) (Compound 97)

Step 1: 1-benzyl-4-methyl-pyrrolidin-2-one

A100 mL flask was charged with 4-methylpyrrolidin-2-one (1.52g, 15.33mmol) and anhydrous tetrahydrofuran (30mL) under nitrogen, the mixture was cooled in an ice bath and NaH (811.9mg, 60% w/w, 20.30mmol) was added in small portionsA stirred slurry stirring was facilitated by the addition of an additional amount of tetrahydrofuran (10 mL.) the mixture was stirred in a cooling bath for 1.5h, benzyl bromide (2.2mL, 18.50mmol) was added dropwise by syringe, the mixture was stirred in a cooling bath, allowed to warm slowly to room temperature overnight after 29h, after which the reaction was poured onto ice/water the product was extracted with ethyl acetate (2 x 75mL) and the organic phase was dried over sodium sulfate, filtered and the solvent evaporated the residue was dissolved in dichloromethane and purified by silica gel chromatography using a gradient of ethyl acetate (0% to 100%)/hexane to give 1-benzyl-4-methyl-pyrrolidin-2-one (2.52g, 87%) as a slightly brown oil. ¹H NMR (400 MHz, chloroform-d) 7.37-7.17(m, 5H), 4.44(s, 2H), 3.36(dd, J ═ 9.6, 7.7Hz, 1H), 2.82 (dd, J ═ 9.6, 6.0Hz, 1H), 2.61(dd, J ═ 16.6, 8.6Hz, 1H), 2.40(ddtd, J ═ 8.6, 7.8, 6.9, 6.0Hz, 1H), 2.08(dd, J ═ 16.6, 6.9Hz, 1H), 1.07(d, J ═ 6.8Hz, 3H). ESI-MS M/z calculated 189.11537, Experimental 190.1(M +1)⁺(ii) a Retention time: 1.16min (LC method B).

Step 2: 1-benzyl-3- (3, 3-dimethylbutyl) -4-methyl-pyrrolidin-2-one

A 100mL round bottom flask was vacuum dried with a heat gun and filled with nitrogen. The flask was charged with 1-benzyl-4-methyl-pyrrolidin-2-one (542mg, 2.864mmol) and anhydrous tetrahydrofuran (8 mL). After cooling to-78 ℃, n-butyllithium solution (1.3mL, 2.5M in hexanes, 3.250mmol) was added dropwise, resulting in a red solution, after stirring for 30min at-78 ℃, 1-bromo-3, 3-dimethyl-butane (450 μ L, 3.195 mmol) was added dropwise, the mixture was stirred in a cooling bath, then allowed to warm slowly to room temperature after 22h, the mixture was quenched by addition of saturated aqueous ammonium chloride solution (50mL), the product was extracted with ethyl acetate (3 × 20mL), and the combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo, silica gel column chromatography using a gradient of 0% to 40% ethyl acetate/hexanes to give 1-benzyl-3- (3, 3-bis) as a colorless oil Methylbutyl) -4-methyl-pyrrolidin-2-one (342mg, 44%). ESI-MS M/z calculated 273.20926, Experimental 274.2(M +1)⁺(ii) a Retention time: 2.03min (LC method B).

And step 3: 3- (3, 3-dimethylbutyl) -4-methyl-pyrrolidin-2-one

To a 50mL flask purged with nitrogen containing 1-benzyl-3- (3, 3-dimethylbutyl) -4-methyl-pyrrolidin-2-one (342mg, 1.251 mmol) were added propan-1-amine (6mL) and ethane-1, 2-diamine (500 μ L, 7.479mmol), the solution was cooled to-30 ℃, and one lithium wire (6cm, cut into 6 smaller pieces and flushed with hexane to remove excess oil) was added, the flask was re-fitted with a septum, and the reaction mixture was stirred vigorously while warming slightly to-20 ℃. A blue color eventually formed around the lithium wire, which approximately penetrated into the solution, and the reaction was stirred until the solution remained dark blue (about 20 min). Water (about 15mL) was added, the larger lithium fragment was removed, and the mixture was allowed to warm to room temperature and stirred for 10min the crude mixture was extracted with ethyl acetate (3 × 25mL) the combined organic extracts were washed with water (15mL), dried over sodium sulfate, filtered and concentrated in vacuo to give crude 3- (3, 3-dimethylbutyl) -4-methyl-pyrrolidin-2-one as a yellow oil (388 mg, 169%) which was used without further purification. ESI-MS M/z calculated 183.16231, Experimental 184.1(M +1) ⁺(ii) a Retention time: 1.43min (LC method B).

And 4, step 4: (14S) -8- [3- (3, 3-dimethylbutyl) -4-methyl-2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (hydrochloride) (Compound 97)

To the crude 3- (3, 3-dimethyl) benzeneVial of methylbutyl) -4-methyl-pyrrolidin-2-one (22mg, 0.1200mmol) was charged with (14S) -8-chloro-12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1- (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (25mg, 0.05373 mmol), (5-diphenylphosphinyl-9, 9-dimethyl-xanthen-4-yl) -diphenyl-phosphane (8mg, 0.01383 mmol), (1E, 4E) -1, 5-diphenylpenta-1, 4-dien-3-one; palladium (13mg, 0.01420mmol), Cs₂CO₃(23 mg, 0.07059mmol) and dioxane (1 mL). The headspace was purged with nitrogen, the vial was capped, and the reaction mixture was stirred at 120 ℃ for 18h ₁₈Reverse phase, 1% to 99% acetonitrile/water + hydrochloric acid modifier) followed by vacuum concentration of the pure fractions and further purification of the residue by silica gel chromatography (0% to 70% ethyl acetate/hexanes) to give (14S) -8- [3- (3, 3-dimethylbutyl) -4-methyl-2-oxopyrrolidin-1-yl as an off-white solid]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (hydrochloride) (compound 97) (2mg, 6%). ESI-MS M/z calculated 596.31445, Experimental 597.2(M +1)⁺(ii) a Retention time: 2.32min (LC method B).

Example 141: preparation of (14S) -12, 12-dimethyl-8- {3- [ (1-methylcyclohexyl) methyl]-2-oxopyrrolidin-1-yl } -2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 101)

Step 1: 1-benzyl-3-diethoxyphosphoryl-pyrrolidin-2-one

To a stirred solution of LDA (30mL, 2.0M, 60.00 mmol) in anhydrous tetrahydrofuran (140mL) at-78 deg.C over 5min in a 250mL flask under nitrogen was added dropwise a solution of 1-benzylpyrrolidin-2-one (5.000g, 28.53mmol) in anhydrous tetrahydrofuran (5 mL). The orange solution was stirred for 1h and 1- [ chloro (ethoxy) phosphoryl was added dropwise over 5min ]A solution of oxyethane (5.170g, 29.96mmol) in anhydrous tetrahydrofuran (5mL) the reaction was warmed to ambient temperature and stirred for 18h, quenched with cold ice water (50mL) and acidified to about pH 2.0 by addition of 1.0M aqueous hydrochloric acid, the aqueous layer was separated and extracted with ethyl acetate (3 × 50mL), the combined organic extracts were dried (sodium sulfate), filtered and concentrated under reduced pressure to give the crude product (8.74g), purified by flash silica gel column chromatography (first over 40min attempted with 10% to 100% ethyl acetate/hexane but this material did not appear, then to 0% to 10% methanol/CH)₂Cl₂With the product eluted) to give the desired 1-benzyl-3-diethoxyphosphoryl-pyrrolidin-2-one as an orange viscous oil (3.31g, 37%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)7.38-7.31(m, 2H), 7.31-7.25(m, 1H), 7.25-7.21(m, 2H), 4.49(dd, J ═ 15.1, 1.4Hz, 1H), 4.30(d, J ═ 15.1Hz, 1H), 4.15-3.98(m, 4H), 3.31-3.14(m, 3H), 2.34-2.19(m, 1H), 2.19-2.04 (m, 1H), 1.22 (two sets of t, J ═ 7.2Hz, 6H). ESI-MS M/z calculated 311.12863, Experimental 312.2(M +1)⁺(ii) a Retention time: 0.93min (LC method B).

Step 2: 1-benzyl-3- [ (1-methylcyclohexyl) methylene ] pyrrolidin-2-one

To 1-benzyl-3-diethoxyphosphoryl-pyrrolidin-2-one in three portions (to slow gas evolution) at 5 deg.C (ice-water bath) under nitrogen in a 50mL flask(300mg, 0.9637mmol) to a stirred solution in anhydrous tetrahydrofuran (10 mL) was added sodium hydride (42.40mg, 47.11. mu.L, 1.060mmol, 60% dispersed in mineral oil). After stirring for 10min, a solution of 1-methylcyclohexanecarboxaldehyde (182.5mg, 1.446 mmol) in anhydrous tetrahydrofuran (2mL) was added dropwise over 3 min. Then stirred at this temperature for 3h and with NH₄The combined organics were washed successively with water (15mL) and brine (15mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude olefin product. Removal of volatiles gave 1-benzyl-3- [ (1-methylcyclohexyl) methylene as a yellow viscous oil and as a mixture of the E and Z isomers]Pyrrolidin-2-one (265mg, 97%). ESI-MS M/z calculated 283.1936, Experimental 284.2(M +1)⁺(ii) a Retention time: 1.98min (LC method B).

And step 3: 1-benzyl-3- [ (1-methylcyclohexyl) methyl ] pyrrolidin-2-one

A50 mL three-necked flask was charged with 1-benzyl-3- [ (1-methylcyclohexyl) methylene ] pyrrolidin-2-one (260mg, 0.9174mmol) and anhydrous methanol (15mL) as a mixture of the E and z isomers under nitrogen, the flask was purged with nitrogen, followed by addition of palladium (100mg, 0.09397mmol, 10%/active carbon) under nitrogen, and stirring at 50 ℃ for 2 days under hydrogen (balloon). The reaction was cooled to ambient temperature and the flask was purged with hydrogen then filtered through a pad of celite the filtrate was concentrated to give crude 1-benzyl-3- [ (1-methylcyclohexyl) methyl ] pyrrolidin-2-one (138mg, 53%) as a brown gum which was used in the next step without further purification.

ESI-MS M/z calculated 285.20926, Experimental 286.3(M +1)⁺(ii) a Retention time: 1.98min (LC method B).

And 4, step 4: 3- [ (1-methylcyclohexyl) methyl ] pyrrolidin-2-one

A50 mL flask was charged with 1-benzyl-3- [ (1-methylcyclohexyl) methyl group in order at ambient temperature under nitrogen]Pyrrolidin-2-one (164mg, 0.5746mmol), propan-1-amine (5mL) and ethane-1, 2-diamine (250. mu.L, 3.740 mmol). The solution was cooled to-35 ℃ (dry ice-acetone bath with 1 or 2 dry ice pellets added intermittently to keep the temperature stable) and at the same time lithium was added (40mg, 5.763mmol, wire, roughly rinsed with hexane, then now cut into small pieces.) blue started to develop around small pieces of lithium and the deep blue color became persistent after 1 h-35 ℃ the reaction was quenched with saturated ammonium chloride (5mL) and allowed to warm to ambient temperature the volatiles were removed under reduced pressure and the aqueous residue was extracted with ethyl acetate (3 × 20 mL.) the combined organics were washed with brine (10mL), dried over anhydrous sodium sulfate and the volatiles were removed under reduced pressure after vacuum drying to obtain crude 3- [ (1-methylcyclohexyl) methyl ] methyl as a white semi-solid ]Pyrrolidin-2-one (78mg, 70%) and used without further purification ESI-MS calculated M/z 195.16231, Experimental 196.1 (M +1)⁺(ii) a Retention time: 1.47min (LC method B).

And 5: (14S) -12, 12-dimethyl-8- {3- [ (1-methylcyclohexyl) methyl group]-2-oxopyrrolidin-1-yl } -2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 101)

A4 mL vial was charged with (14S) -8-chloro-12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (25mg, 0.05373 mmol), 3- [ (1-methylcyclohexyl) methyl]Pyrrolidin-2-ones(10mg，0.05120mmol)、Pd₂(dba)₃(8 mg, 0.008736mmol), xanthphos (5mg, 0.008641mmol), cesium carbonate (87.52mg, 0.2686 mmol) and anhydrous dioxane (0.4 mL). The mixture was aerated with nitrogen for 1 to 2min, capped and stirred at 120 ℃ for 15h the reaction was diluted with dimethyl sulfoxide (1000 μ L), microfiltered and subjected to reverse phase preparative HPLC (C) using a gradient of acetonitrile in water (1% to 99% over 15min) and hydrochloric acid as modifier (ca)₁₈). The pure fractions were collected and combined, a small amount of brine was added and the organic solvent was evaporated the product was extracted with dichloromethane and the organic phase was dried over sodium sulfate followed by filtration the filtrate was evaporated to give 10mg of a solid. The product was further purified by flash chromatography on silica gel using a gradient of methanol/dichloromethane (0% to 5% over 30min) to give (14S) -12, 12-dimethyl-8- {3- [ (1-methylcyclohexyl) methyl ] as an off-white solid ]-2-oxopyrrolidin-1-yl } -2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 101) (6.4mg, 19%).¹H NMR (400 MHz, dimethylsulfoxide-d)₆)12.41(s, 1H), 7.68(dd, J ═ 8.5, 1.4Hz, 1H), 7.61-7.47(M, 2H), 7.04(d, J ═ 7.1Hz, 1H), 6.97 (width d, J ═ 9.0Hz, 1H), 6.70(d, J ═ 8.5Hz, 1H), 4.11-3.65(M, 3H), 3.10(br s, 1H), 2.94(d, J ═ 13.3Hz, 1H), 2.75-2.57(M, 2H), 2.43-2.28(M, 1H), 2.10(br s, 1H), 2.02-1.93(M, 1H), 1.89-1.64(M, 3H), 1.64-1.37 (M, 13H), 1.35 (M, 1.35, 1H), 7.83 (M, 3H), 7.8H, 3H), 7.83 (M, 3H), 3H, 7.8, 3H, 7.84, 7, 3H, 3H⁺(ii) a Retention time: 2.34min (LC method B).

Example 142: preparation of 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda⁶-thia-3, 9, 11, 21-tetraazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 103) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda⁶-thia-3, 9, 11, 21-tetraazatetracyclo [18.2.2.111,14.05，10]pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 104)

Step 1: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda⁶-thia-3, 9, 11, 21-tetraazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 103) and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda⁶-thia-3, 9, 11, 21-tetraazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 104)

Racemic 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl) was chromatographed by SFC using ChiralCel OD-H (250 × 10mm column, 5 μm particle size) and a 42% acetonitrile/methanol (90: 10)/58% carbon dioxide mobile phase (10mL/min over 8.0min) (infusion volume 70 μ L, 24mg/mL solution in acetonitrile/methanol (90: 10))]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda ⁶-thia-3, 9, 11, 21-tetraazatetracyclo [18.2.2.111, 14.05, 10]The pentacosate-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (71mg, 0.1095mmol) was subjected to chiral separation to give 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] ketone as the first enantiomer to be eluted as a white solid]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda⁶-thia-3, 9, 11, 21-tetraazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 103) (19.77mg, 56%); ESI-MS M/z calculated 648.2342, Experimental 649.2(M +1)⁺(ii) a Retention time: 2.38min (LC method E), and 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid of the second enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda⁶-thia-3, 9, 11, 21-tetraazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 104) (20.25mg, 57%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.46(s, 1H), 8.77(s, 1H), 8.19(d, J ═ 2.8Hz, 2H), 7.88(d, J ═ 8.3Hz, 1H), 7.03(d, J ═ 8.7Hz, 1H), 6.92(d, J ═ 8.3Hz, 1H), 6.11(d, J ═ 2.7Hz, 1H), 4.31(t, J ═ 7.0Hz, 2H), 2.41 (dd, J ═ 8.3, 5.3Hz, 1H), 2.07(t, J ═ 7.0Hz, 3H), 2.04-1.98(m, 1H), 1.73(d, J ═ 6.4 Hz, 2H), 1.67(dd, J ═ 7.9, 4.9, 1H, 1.55(m, 1H), 1.73(d, J ═ 6.4 Hz, 2H), 1.67(dd, 7.9, 4, 1H), 1.9, 1H, 1.6, 6.4H), 1.7, 6H, 1.7 (d, 3H), 1.7, 1H, 6, 1H, 1.6, 6, 1H), 1H, 7, 6H, 1H, 7H, 1H, 6H, 1H, 1.7H, 1H, 7H, 1H. ESI-MS M/z calculated 648.2342, Experimental 649.2(M +1) ⁺(ii) a Retention time: 2.38min (LC method E).

Example 143: preparation of 8, 8-dimethyl-12- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -18 lambda⁶-thia-2, 9, 11, 17, 23-pentaazatetracyclo [17.3.1.05, 9.010, 15 [ ]]Tricosane-1 (23), 10(15), 11, 13, 19, 21-hexaen-16, 18, 18-trione (compound 108), 8-dimethyl-12- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -18 lambda⁶-thia-2, 9, 11, 17, 23-pentaazatetracyclo [17.3.1.05, 9.010, 15 [ ]]Tricosane-1 (23), 10(15), 11, 13, 19, 21-hexaen-16, 18, 18-trione (enantiomer 1) (compound 116) and 8, 8-dimethyl-12- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -18 lambda⁶-thia-2, 9, 11, 17, 23-pentaazatetracyclo [17.3.1.05, 9.010, 15 [ ]]Tricosane-1 (23), 10(15), 11, 13, 19, 21-hexaene-16, 18, 18-trione (enantiomer 2) (compound 117)

Step 1: 2- (1-hydroxy-5, 5-dimethyl-pyrrolidin-2-yl) acetonitrile

N-butyllithium (127mL, 2.5M, 317.5mmol) was added dropwise to anhydrous tetrahydrofuran (270mL) cooled at-78 deg.C, during the addition, the internal temperature was kept below-65 deg.C. Acetonitrile (13.13g, 16.7mL, 319.8mmol) was then added slowly, keeping the internal temperature below-70 ℃. A white precipitate of lithiated acetonitrile was observed after half of the acetonitrile was added after 30min at-78 deg.C, a solution of 2, 2-dimethyl-1-oxoanion-3, 4-dihydropyrrol-1-ium (11.20g, 99mmol) in anhydrous tetrahydrofuran (15mL) was added at a rate such that the internal temperature did not rise above-70 deg.C. The yellow suspension was stirred at-78 ℃ for 1h, then quenched with a saturated solution of ammonium chloride (150mL) after warming to room temperature, the two layers were separated. The aqueous layer was extracted with ethyl acetate (2X 150 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude 2- (1-hydroxy-5, 5-dimethyl-pyrrolidin-2-yl) acetonitrile (17g, by filtration) as a brown oil ¹H NMR gave about 80% purity, 89% yield), which was used directly in the next step without further purification.¹H NMR(300MHz，CDCl₃)1.04(s，3H)，1.18(s，3H)，1.48-1.67 (m，3H)，1.99-2.06(m，1H)，2.59(d，J＝5.2Hz，2H)，3.17-3.26(m，1H)，4.59(br.s.， 1H)。

Step 2: 2- (5, 5-dimethylpyrrolidin-2-yl) acetonitrile

Zinc (4.9g, 0.6869mL, 74.935mmol) was added in portions to a solution of 2- (1-hydroxy-5, 5-dimethyl-pyrrolidin-2-yl) acetonitrile (1.8g, 8.1707mmol) in acetic acid (21mL) in an ice-water bath and the mixture was kept warmTo room temperature and vigorously stirred, and heated to 30 ℃ for 6h, the crude mixture was filtered and concentrated under reduced pressure to afford the crude product, which was neutralized with 5% sodium bicarbonate (100mL) and extracted with dichloromethane (2 × 100 mL). The organics were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the crude 2- (5, 5-dimethylpyrrolidin-2-yl) acetonitrile (0.9g, 70%) as a pale yellow semi-solid, ESI-MS calculated M/z 138.1157, experimental 139.2(M +1)⁺(ii) a Retention time: 0.312min (LC method I).

And step 3: 5- (cyanomethyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

Di-tert-butyl dicarbonate (17.4g, 18.32mL, 79.73mmol) is added to a solution of 2- (5, 5-dimethylpyrrolidin-2-yl) acetonitrile (12g, 51% pure, 44.28mmol) and triethylamine (8.712g, 12mL, 86.10mmol) in tetrahydrofuran (100 mL). The reaction was stirred at room temperature over the weekend and the reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran. The residue was purified by silica gel chromatography using a gradient of 0% to 20% ethyl acetate/heptane to give tert-butyl 5- (cyanomethyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate as a light yellow oil (9.5g, 63%). ESI-MS M/z calculated 238.326, Experimental 261.2(M + Na) ⁺(ii) a Retention time: 2.12min (LC method I).

And 4, step 4: 5- (2-aminoethyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

A250 mL round bottom flask was charged with tert-butyl 5- (cyanomethyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (9.1g, 38.2mmol), ammonia (10mL, 7M solution in methanol, 70mmol), methanol (70mL), and Raney's nickel (slurry in water, approximately 4g, taken up with a spatula without precision weighing). the mixture was stirred vigorously at room temperature under 1 atmosphere of H2 (balloon)Day.another addition of raney nickel (slurry in water, approximately 6g, taken up with a spatula without precise weighing) and ammonia (10mL, 7M solution in methanol, 70mmol) was added, the reaction was stirred overnight, the mixture was filtered through a pad of celite, washed with ethyl acetate, the filtrate was concentrated under reduced pressure to give a yellow oil, i.e. tert-butyl 5- (2-aminoethyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (8.16g, 83% yield).¹H NMR(300MHz，CDCl₃) ppm 1.16-1.34(M, 3H), 1.34-1.59 (M, 16H), 1.63-2.00(M, 4H), 2.60-2.75(M, 2H), 3.73-3.90(M, 0.3H), 3.90-4.05(M, 0.6H), two rotamers observed ESI-MS M/z calculated 242.358, experimental 243.2(M +1)⁺(ii) a Retention time: 1.74min (LC method H).

And 5: 2, 2-dimethyl-5- [2- [ (6-sulfamoyl-2-pyridyl) amino ] ethyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 5- (2-aminoethyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (500.0mg, 2.063mmol) in N, N-dimethylformamide (5mL) was added 6-fluoropyridine-2-sulfonamide (302.8mg, 1.719 mmol) followed by potassium carbonate (712.9mg, 5.158mmol), the flask was capped with a septum and heated in an oil bath at 90 ℃ for 14h under a nitrogen balloon. The organics were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexane to 100% ethyl acetate to give 2, 2-dimethyl-5- [2- [ (6-sulfamoyl-2-pyridyl) amino as a white solid]Ethyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (428 mg, 62%).¹H NMR (400MHz, chloroform-d) 7.48(t, J ═ 7.9Hz, 1H), 7.18(dd, J ═ 7.2, 3.3Hz, 1H), 6.53(d, J ═ 8.4Hz, 1H), 5.68(d, J ═ 5.8Hz, 1H), 5.50(s, 2H), 4.00(q, J ═ 6.6Hz, 1H), 3.48(dq, J ═ 13.0, 6.9Hz, 1H), 3.20 to 3.06(m, 1H), 2.03 to 1.86(m, 1H), 1.77(t, J ═ 5.3Hz, 1H), 1.59(dq, J ═ 14.4, 7.1Hz, 1H), 1.46(s, 9H) 1.39(s, 3H), 1.28(s, 3H). ESI-MS M/z calculated 398.19876, Experimental 399.24(M +1)⁺(ii) a Retention time: 0.63min (LC method A).

Step 6: 5- [2- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] ethyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (237.6 mg, 0.6323mmol) and carbonyldiimidazole (102.5mg, 0.6323mmol) were combined in tetrahydrofuran (3.0mL) and stirred at 50 ℃ for 90min, after which 2, 2-dimethyl-5- [2- [ (6-sulfamoyl-2-pyridyl) amino]Ethyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (210mg, 0.5269mmol) followed by addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (120.3mg, 118.2 μ L, 0.7904mmol) and the reaction stirred at room temperature for 18 h. The organics were separated, dried over sodium sulfate, filtered and evaporated, followed by chromatography on silica gel using a gradient of 100% dichloromethane to 20% methanol/dichloromethane to give 5- [2- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] as a white solid ]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Ethyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (321mg, 81%).¹H NMR (400MHz, chloroform-d) 8.22(s, 1H), 8.14(d, J ═ 8.1Hz, 1H), 7.54(d, J ═ 14.9Hz, 2H), 7.39(d, J ═ 19.1Hz, 1H), 6.54(s, 1H), 6.06(s, 1H), 5.89(d, J ═ 2.8Hz, 1H), 4.36(t, J ═ 7.2Hz, 2H), 3.90(s, 1H), 3.29(s, 1H), 3.09(s, 1H), 2.08(t, J ═ 7.3Hz, 2H), 1.86(s, 4H), 1.69(s, 1H), 1.52(s, 1H), 1.37(d, J ═ 37.2, 12H), 1.22(s, 4H), 1.06 (s, 0.06H), 0.70H, 0.78H, 0.70H, 0 m. ESI-MS M/z calculated 755.248, Experimental 756.2(M +1)⁺(ii) a Retention time: 0.87min (LC method A)

And 7: 8, 8-dimethyl-12- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -18 lambda⁶-thia-2, 9, 11, 17, 23-pentaazatetracyclo [17.3.1.05, 9.010, 15 [ ]]Tricosane-1 (23), 10(15), 11, 13, 19, 21-hexaene-16, 18, 18-trione (compound 108)

Reacting 5- [2- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] at room temperature]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group ]Ethyl radical]A solution of tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (320 mg, 0.4231mmol) in dichloromethane (2.667mL) and trifluoroacetic acid (482.4mg, 323.8 μ L, 4.231 mmol) was stirred for 4h

Molecular sieves and stirring the reaction mixture for 10min then cesium fluoride (192.8mg, 1.269mmol) and potassium carbonate (175.4mg, 1.269mmol) were added and the reaction mixture was heated at 130 ℃ for 24 h. The reaction mixture was filtered through celite, and the celite bed was washed with ethyl acetate. The resulting brown residue was purified by silica gel column chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate to give 8, 8-dimethyl-12- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a pale yellow solid]Ethoxy } -1H-pyrazol-1-yl) -18 lambda⁶-thia-2, 9, 11, 17, 23-pentaazatetracyclo [17.3.1.05, 9.010, 15 [ ]]Tricosane-1 (23), 10(15), 11, 13, 19, 21-hexaen-16, 18, 18-trione (compound 108) (145mg, 55%). ¹H NMR (400MHz, chloroform-d) 13.95 (s, 1H), 8.50(s, 1H), 8.24(d, J ═ 2.8Hz, 1H), 7.63(s, 1H), 7.52(dd, J ═ 8.3, 7.3Hz, 1H), 7.28(d, J ═ 7.3Hz, 1H), 6.49(d, J ═ 7.3Hz, 1H), and combinations thereof8.3Hz, 1H), 5.96(d, J ═ 2.8Hz, 1H), 4.85 (s, 1H), 4.42(t, J ═ 7.1Hz, 2H), 4.24(s, 1H), 3.01(s, 2H), 2.59(d, J ═ 19.1Hz, 1H), 2.32(s, 1H), 2.10(t, J ═ 7.1Hz, 2H), 1.91(s, 2H), 1.60(s, 3H), 1.13(s, 3H), 1.06-1.00 (M, 2H), 0.77-0.70(M, 2H), ESI-MS M/z calculated value 619.2189, experimental value 620.06 (M +1)⁺(ii) a Retention time: 1.87min (LC method B).

And 8: 8, 8-dimethyl-12- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -18 lambda⁶-thia-2, 9, 11, 17, 23-pentaazatetracyclo [17.3.1.05, 9.010, 15 [ ]]Tricosane-1 (23), 10(15), 11, 13, 19, 21-hexaen-16, 18, 18-trione (enantiomer 1) (compound 116) and 8, 8-dimethyl-12- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -18 lambda⁶-thia-2, 9, 11, 17, 23-pentaazatetracyclo [17.3.1.05, 9.010, 15 [ ]]Tricosane-1 (23), 10(15), 11, 13, 19, 21-hexaene-16, 18, 18-trione (enantiomer 2) (compound 117)

Rac 8, 8-dimethyl-12- (3- {2- [1- (trifluoromethyl) cyclopropyl) was chromatographed by SFC using ChiralPak AS-H (250 × 21.2mm column, 5 μm particle size) and 25% acetonitrile/methanol (90: 10)/75% carbon dioxide mobile phase (70mL/min) (injection volume 500 μ L, 32 mg/mL solution in acetonitrile/methanol (90: 10))]Ethoxy } -1H-pyrazol-1-yl) -18 lambda⁶-thia-2, 9, 11, 17, 23-pentaazatetracyclo [17.3.1.05, 9.010, 15 [ ]]Ditridec-1- (23), 10(15), 11, 13, 19, 21-hexaen-16, 18, 18-trione (compound 108) (145mg) was subjected to chiral separation to give 8, 8-dimethyl-12- (3- {2- [1- (trifluoromethyl) cyclopropyl ] ketone as the first enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -18 lambda⁶-thia-2, 9, 11, 17, 23-pentaazatetracyclo [17.3.1.05, 9.010, 15 [ ]]Tricosane-1 (23), 10(15), 11, 13, 19, 21-hexaene-16, 18, 18-trione (enantiomer 1) (compound 116) (46.5mg, 34%);¹H NMR (400MHz, chloroform-d) 13.88(s, 1H), 8.50(s, 1H), 8.24(d, J ═ 2.8Hz, 1H), 7.64(s, 1H), 7.52(dd, J ═ 8.4, 7.3Hz, 1H), 7.28(s, 1H), 6.50(d, J ═ 8.3Hz, 1H), 5.96(d, J ═ 2.8Hz, 1H), 4.89(s, 1H), 4.48-4.38(M, 2H), 4.24(s, 1H), 3.01(s, 2H), 2.59(d, J ═ 23.4Hz, 1H), 2.32(s, 1H), 2.11(t, J ═ 7.1Hz, 2H), 1.92(brs, 2H), 1.61 (J ═ 23.4Hz, 1H), 2.32(s, 1H), 2.11(t, J ═ 7.1Hz, 2H), 1H), 1.61 (brs, 2H), 6H, 7.0, 7.7.0 (M-19H), 5 (M, 1H), 13 (M-19 (M, 1H), 2H ⁺(ii) a Retention time: 1.86min (LC method B) and 8, 8-dimethyl-12- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as the second enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -18 lambda⁶-thia-2, 9, 11, 17, 23-pentaazatetracyclo [17.3.1.05, 9.010, 15 [ ]]Tricosane-1 (23), 10(15), 11, 13, 19, 21-hexaen-16, 18, 18-trione (enantiomer 2) (compound 117) (66.1mg, 50%);¹h NMR (400MHz, chloroform-d) 13.87(s, 1H), 8.50(s, 1H), 8.25(s, 1H), 7.63(s, 1H), 7.54(s, 1H), 7.28(s, 1H), 6.52(s, 1H), 5.96(s, 1H), 4.81(s, 1H), 4.42(s, 2H), 4.25(s, 1H), 3.04(s, 2H), 2.58(s, 1H), 2.33(s, 1H), 2.11(t, J ═ 5.0Hz, 2H), 1.92(s, 2H), 1.60(s, 6H), 1.14(s, 2H), 1.03(d, J ═ 5.6Hz, 2H), 0.75(s, 2H). ESI-MS M/z calculated 619.2189, Experimental 620.1(M +1)⁺(ii) a Retention time: 1.86min (LC method B).

Example 144: preparation of (14S) -12, 12, 20-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -18-oxa-2. lambda⁶-thia-3, 9, 11, 23-tetraazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 109)

Step 1: (4S) -2, 2-dimethyl-4- [3- [ (3-methyl-6-sulfamoyl-2-pyridyl) oxy ] propyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

To N, N-dimethylformamide (6mL) containing tert-butyl (4S) -4- (3-hydroxypropyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (496mg, 1.927mmol) stirred under nitrogen atmosphere was added NaH (154.1mg, 171.2 μ L, 3.854mmol) portionwise and the mixture was stirred at room temperature for 15min, followed by 6-chloro-5-methyl-pyridine-2-sulfonamide (398.2mg, 1.927mmol) and the resulting mixture stirred at room temperature for 80 min. To the stirred solution was added NaH (77.07mg, 85.63 μ L, 1.927mmol) again at room temperature and the reaction tube was capped, the resulting mixture was stirred at 100 ℃ for 14h, the cooled reaction mixture was poured into 1N citric acid and extracted with ethyl acetate (2 ×), the organic fractions were combined, dried (sodium sulfate), filtered and concentrated in vacuo to a clear oil that was purified by silica gel chromatography using a mobile phase gradient of 100% hexane to 100% ethyl acetate to give (4S) -2, 2-dimethyl-4- [3- [ (3-methyl-6-sulfamoyl-2-pyridyl) oxy]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (336mg, 41%).¹H NMR (400MHz, dimethylsulfoxide-d) ₆) 7.74(dd, J ═ 7.4, 1.0Hz, 1H), 7.39(d, J ═ 7.4Hz, 1H), 7.29(s, 2H), 4.36(s, 2H), 3.58 (q, J ═ 8.4, 7.9Hz, 1H), 2.81(q, J ═ 10.1Hz, 1H), 2.20(t, J ═ 1.8Hz, 4H), 1.96(d, J ═ 26.1Hz, 1H), 1.75(dt, J ═ 14.2, 6.9Hz, 2H), 1.46(q, J ═ 7.6, 7.1Hz, 2H), 1.37(t, J ═ 10.7Hz, 13H), 1.25(s, 3H). ESI-MS M/z calculated 427.21408, Experimental 428.21(M +1)⁺(ii) a Retention time: 0.72min (LC method A).

Step 2: (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -3-methyl-2-pyridinyl ] oxy ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (175.8 mg, 0.4678mmol) and carbonyldiimidazole (75.85mg, 0.4678mmol) were combined in tetrahydrofuran (4.678 mL) and stirred at 50 ℃ for 60 min. Subsequently, (4S) -2, 2-dimethyl-4- [3- [ (3-methyl-6-sulfamoyl-2-pyridyl) oxy was added]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (200mg, 0.4678mmol) was added followed by 1, 8-diazabicyclo [5.4.0]Undec-7-ene (71.22mg, 69.96 μ L, 0.4678mmol) and the reaction was heated at 50 ℃ for 15 h. The reaction was diluted with ethyl acetate and washed with 1M citric acid solution followed by brine. The organics were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexane to 75% ethyl acetate/hexane to give (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] as an off-white solid ]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-3-methyl-2-pyridinyl]Oxy radical]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (296mg, 81%). ESI-MS calculated M/z 784.2633, Experimental 785.1(M +1)⁺(ii) a Retention time: 0.84 min (LC method A).

And step 3: (14S) -12, 12, 20-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -18-oxa-2. lambda⁶-thia-3, 9, 11, 23-tetraazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 109)

Reacting (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-3-methyl-2-pyridinyl]Oxy radical]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (296mg, 0.3769mmol) was dissolved in dichloromethane (5mL) and hydrochloric acid (3.5 mL, 4M in dioxane, 14.00mmol) was added to the mixture and stirred at room temperature for 30 min. The reaction solution was concentrated to dryness in vacuo, and the resultant was mixed with potassium carbonate (313mg, 2.265mmol), cesium fluoride (93mg, 0.6122 mmol),

Molecular sieves and dimethylsulfoxide (6mL) were combined in a vial, purged with nitrogen, capped, heated to 140 ℃, and stirred for 16 h. Cooled to room temperature and the reaction mixture filtered, followed by reverse phase preparative chromatography using C ₁₈Column (20% -99% acetonitrile-water +5mM hydrochloric acid) to give (14S3-12, 12, 20-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl acetate as a white solid]Ethoxy } -1H-pyrazol-1-yl) -18-oxa-2. lambda⁶-thia-3, 9, 11, 23-tetraazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 109) (78mg, 32%).¹H NMR (400 MHz, dimethylsulfoxide-d)₆)12.73(s, 1H), 8.21(d, J ═ 2.8Hz, 1H), 7.86(dd, J ═ 8.3, 7.0Hz, 2H), 7.58(d, J ═ 7.4Hz, 1H), 6.94(d, J ═ 8.2Hz, 1H), 6.12(d, J ═ 2.7Hz, 1H), 5.18(t, J ═ 12.2Hz, 1H), 4.32(t, J ═ 7.0Hz, 2H), 3.96(d, J ═ 11.1Hz, 1H), 3.14(t, J ═ 8.4Hz, 1H), 2.56(d, J ═ 10.8Hz, 1H), 2.18(s, 3H), 2.11-2.01(m, 3H), 1.92 (m, 1.85, 1H), 2.5 (d, J ═ 5, 5H), 5.5 (d, J ═ 10.8Hz, 1H), 2.18 (d, 3.8H, 3H, 5H, 5 (m ═ 3.8H, 5H, 1H, 5H), 2.5, 5H), experimental value 649.41(M +1)⁺(ii) a Retention time: 2.38min (LC method B).

Example 145: preparation of 20, 20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl [) ]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (compound 110)

Step 1: 2, 2-dimethyl-4- [3- (4-sulfamoylpyrazol-1-yl) propyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

Tert-butyl 2, 2-dimethyl-4- (3-methylsulfonyloxypropyl) pyrrolidine-1-carboxylate (490mg, 1.461mmol) and 1H-pyrazole-4-sulfonamide (215mg, 1.461mmol) were dissolved in N, N-dimethylformamide (15mL), followed by dissolution of potassium carbonate (710mg, 5.137mmol) and stirred at 50 ℃ in a 150mL sealed vessel for 48H, cooled to room temperature, then poured into water (100mL) and extracted with ethyl acetate (2 × 100mL), the organic layers were combined, washed with water (2 × 100mL), dried (sodium sulfate), filtered and concentrated -yl) propyl]Pyrrolidine-1-carboxylic acid tert-butyl ester (400mg, 71%).¹H NMR (400MHz, dimethylsulfoxide-d)₆) 8.20(s, 1H), 7.71(s, 1H), 7.23(s, 2H), 4.14(t, J ═ 6.7Hz, 2H), 3.54(dd, J ═ 18.0, 10.3Hz, 1H), 2.74(q, J ═ 10.2Hz, 1H), 2.10(dt, J ═ 10.1, 6.4Hz, 1H), 1.87(td, J ═ 13.0, 6.1Hz, 1H), 1.81-1.69(M, 2H), 1.38(d, J ═ 10.5Hz, 10H), 1.34(d, J ═ 10.7 Hz, 3H), 1.24(s, 5H), ESI-MS M/z calculated value 386.19876, experimental value 387.2(M +1) ⁺(ii) a Retention time: 1.49min (LC method E).

Step 2: 4- [3- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] pyrazol-1-yl ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (335mg, 0.8916mmol) and carbonyldiimidazole (143mg, 0.8819mmol) were combined in tetrahydrofuran (4.5mL) and stirred at room temperature for 60min, then 2, 2-dimethyl-4- [3- (4-sulfamoylpyrazol-1-yl) propyl ] was added]Pyrrolidine-1-carboxylic acid tert-butyl ester (200mg, 0.5175mmol), followed by addition of 1,8-diazabicyclo [5.4.0 ]]Undec-7-ene (225 μ L, 1.505mmol) and the reaction was heated at 50 ℃ for 18 h. The organics were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexane to 100% ethyl acetate to give 4- [3- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] as an off-white solid]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical ]Pyrazol-1-yl]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (201mg, 52%). ESI-MS calculated M/z 743.248, Experimental 744.2(M +1)⁺(ii) a Retention time: 1.84min (LC method E).

And step 3: 20, 20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (compound 110)

4- [3- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] group]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Pyrazol-1-yl]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (200mg, 0.2687 mmol) was dissolved in dichloromethane (5.0mL) and to this mixture was added hydrochloric acid (2.5mL, 4M in dioxane, 10.00mmol) and stirred at room temperature for 30min the mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate and then added 2M aqueous sodium carbonate (5mL) to a pH of about 10. the solution was extracted with ethyl acetate (2 × 10mL), washed with brine, then dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure the resulting material and potassium carbonate (190mg, 1.375mmol), cesium fluoride (65mg, 0.4279mmol),

Molecular sieves and dimethylsulfoxide (6mL) were combined in a vial, purged with nitrogen, capped, heated to 155 ℃, and stirred for 20h.The organics were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexane to 80% ethyl acetate/hexane, followed by a second column using a gradient of 100% dichloromethane to 10% methanol/dichloromethane to give 20, 20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (compound 110) (59.6mg, 36%).¹H NMR (400MHz, dimethylsulfoxide-d)₆) 12.24(s, 1H), 8.55(s, 1H), 8.18(d, J ═ 2.8Hz, 1H), 7.88(s, 1H), 7.74(d, J ═ 8.2Hz, 1H), 6.89(d, J ═ 8.2Hz, 1H), 6.10(d, J ═ 2.7Hz, 1H), 4.31(t, J ═ 7.0Hz, 3H), 4.07(t, J ═ 11.5Hz, 1H), 2.17(dd, J ═ 7.3, 5.2Hz, 1H), 2.07(t, J ═ 7.1Hz, 4H), 1.93(t, J ═ 9.3Hz, 1H), 1.87-1.69(m, 2H), 1.60(d, J ═ 12.4, 1H), 1.49 (t, J ═ 1.0, 1H), 1.49 (d, 1H), 1.0.1H, 1H, and 1H. ESI-MS M/z calculated 607.2189, Experimental 608.2(M +1) ⁺(ii) a Retention time: 2.07min (LC method E).

Example 146: preparation of (18S) -20, 20, 22-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (atropisomer 1) (compound 111), (18S) -12, 20, 20-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (compound 112) and (18S) -20, 20, 22-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] ketone]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]A mixture of the twenty-two carbons-2, 4,6, 11(22), 12-pentaene-8, 10, 10-trione (atropisomer 2) (Compound 113)

Step 1: (4S) -4- [3- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -3-methyl-pyrazol-1-yl ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester and (4S) -4- [3- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -5-methyl-pyrazol-1-yl ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (mixture of regioisomers)

To a solution containing 2-chloro-N- [ (5-methyl-1H-pyrazol-4-yl) sulfonyl group]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]A flask of pyridine-3-carboxamide (900mg, 1.734mmol), potassium carbonate (720mg, 5.210 mmol) and dimethyl sulfoxide (14mL) was charged with a solution of tert-butyl (4S) -2, 2-dimethyl-4- (3-methylsulfonyloxypropyl) pyrrolidine-1-carboxylate (699mg, 2.084mmol) in dimethyl sulfoxide (2mL) and the reaction was stirred at 95 ℃ overnight. The reaction was cooled to room temperature, filtered, and purified by HPLC (30% -99% acetonitrile/water + 0.1% hydrochloric acid modifier) to provide (4S) -4- [3- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] methyl ] ethyl ester]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-3-methyl-pyrazol-1-yl]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester and (4S) -4- [3- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-5-methyl-pyrazol-1-yl]Propyl radical]Tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (mixture of regioisomers) (524.1 mg, 40%). ESI-MS M/z calculated 757.2636, Experimental 758.5(M +1)⁺(ii) a Retention time: 1.93 min (LC method G).

Step 2: 2-chloro-N- [1- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] propyl ] -3-methyl-pyrazol-4-yl ] sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide and 2-chloro-N- [1- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] propyl ] -5-methyl-pyrazol-4-yl ] sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide (mixture of regioisomers Thing)

To a solution containing (4S) -4- [3- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-3-methyl-pyrazol-1-yl]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester and (4S) -4- [3- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-5-methyl-pyrazol-1-yl]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (mixture of regioisomers) (524mg, 0.6911mmol) in a flask was added dichloromethane (10mL) and trifluoroacetic acid (2.7 mL, 35.05mmol). The reaction was stirred at room temperature for 1h then evaporated to dryness and quenched with saturated sodium bicarbonate the reaction was extracted 3 times with a solution of dichloromethane: methanol (9: 1), dried over sodium sulfate and evaporated to afford 2-chloro-N- [1- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ]Propyl radical]-3-methyl-pyrazol-4-yl]Sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamides and 2-chloro-N- [1- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl]Propyl radical]-5-methyl-pyrazol-4-yl]Sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (mixture of regioisomers) (435mg, 96%). ESI-MS M/z calculated 657.2112, Experimental 658.3(M +1)⁺(ii) a Retention time: 1.61min (LC method E).

And step 3: (18S) -20, 20, 22-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (atropisomer 1) (compounds111) (18S) -12, 20, 20-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (compound 112) and (18S) -20, 20, 22-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] ketone]Ethoxy } -1H-pyrazol-1-yl) -10 lambda ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (atropisomer 2) (compound 113)

To a 20 dram (dram) vial was added potassium carbonate (458mg, 3.314mmol), cesium fluoride (302mg, 1.988mmol), and 2-chloro-N- [1- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl)]Propyl radical]-3-methyl-pyrazol-4-yl]Sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamides and 2-chloro-N- [1- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl]Propyl radical]-5-methyl-pyrazol-4-yl]Sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (mixture of regioisomers) (435mg, 0.6610mmol) in dimethylsulfoxide (17.50 mL). The reaction was cooled to room temperature, filtered, and purified by HPLC (30% -80% acetonitrile/water + hydrochloric acid modifier) to provide (18S) -20, 20, 22-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl-4) as the first product to be eluted]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7 ]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (atropisomer 1) (compound 111) (32.5mg, 16%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.39(s， 1H)，8.18(d，J＝2.8Hz，1H)，7.86(s，1H)，7.77(d，J＝8.2Hz，1H)，6.90(d，J＝8.2 Hz，1H)，6.10(d，J＝2.7Hz，1H)，4.38(dt，J＝14.1，3.1Hz，1H)，4.31(t，J＝7.0Hz， 2H)，4.01(td，J＝14.0，2.8Hz，1H)，2.06(qJ ═ 8.0, 7.6Hz, 5H), 1.90-1.71(m, 3H), 1.55(s, 3H), 1.47(s, 3H), 1.45-1.30(m, 2H), 1.10(s, 1H), 0.99-0.93(m, 2H), 0.93-0.85 (m, 2H), three protons are masked by the residual solvent. ESI-MS M/z calculated 621.2345, Experimental 622.3(M +1)⁺(ii) a Retention time: 2.96min (LC method D.) the second product to be eluted was (18S) -12, 20, 20-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] -ethyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (compound 112) (53.9mg, 26%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.18(s, 1H), 8.41(s, 1H), 8.18(d, J ═ 2.8Hz, 1H), 7.75(d, J ═ 8.2Hz, 1H), 6.89(d, J ═ 8.2Hz, 1H), 6.10(d, J ═ 2.7Hz, 1H), 4.31(t, J ═ 7.0Hz, 2H), 4.22(dt, J ═ 13.6, 3.8Hz, 1H), 4.03-3.92(M, 1H), 2.40(s, 3H), 2.22(d, J ═ 11.8Hz, 1H), 2.11-1.91 (M, 5H), 1.83(dt, J ═ 15.7, 7.4Hz, 1H), 1.75(dd, J ═ 11.5, 1H), 2.11-1.91 (M, 5H), 1.83(dt, J ═ 15.7, 7.4Hz, 1H), 1.75(dd, 11, 5, 0.9, 0.0, 0.1H), 1H, 13H, 1 ⁺(ii) a Retention time: 3.01min (LC method D). The third product to be eluted was (18S) -20, 20, 22-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] -amide]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (atropisomer 2) (compound 113) (12.4mg, 6%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.10(s, 1H), 8.18(d, J ═ 2.8Hz, 1H), 7.81 to 7.70 (m, 2H), 6.88(d, J ═ 8.3Hz, 1H), 6.10(d, J ═ 2.8Hz, 1H), 4.40 to 4.26(m, 3H), 4.00 (ddd, J ═ 13.5, 10.2, 2.7Hz, 1H), 2.68(s, 3H), 2.43 to 2.32(m, 1H), 2.07(t, J ═ 7.1Hz, 3H), 1.96 to 1.57(m, 5H), 1.57 to 1.41(m, 8H), 1.00 to 0.84(m, 4H) · (2 are masked by the solvent residue). ESI-MS M/z calculated 621.2345, Experimental 622.4(M +1)⁺(ii) a Retention time: 3.08min (LC method D).

Example 147: preparation 20, 20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (enantiomer 1) (compound 118) and 20, 20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 119)

Step 1: 20, 20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (enantiomer 1) (compound 118) and 20, 20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 119)

Racemic 20, 20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl) was chromatographed by SFC using ChiralPak AS-H (250 × 10mm, 5 μm particle size) and 26% acetonitrile: methanol (90: 10; no modifier)/74% carbon dioxide mobile phase (10mL/min over 8.0min) (injection volume 70 μ L, 24mg/mL solution in methanol/dimethyl sulfoxide (90: 10))]Ethoxy } -1H-pyrazol-1-yl) -10 lambda ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]The chiral separation of the docosane-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (57mg, 0.09287mmol) gave the first to be elutedEnantiomeric 20, 20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (enantiomer 1) (compound 118) (20.76mg, 74%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.24(s, 1H), 8.53(s, 1H), 8.18(d, J ═ 2.8Hz, 1H), 7.87(s, 1H), 7.73 (d, J ═ 8.2Hz, 1H), 6.88(d, J ═ 8.2Hz, 1H), 6.09(d, J ═ 2.7Hz, 1H), 4.30(t, J ═ 7.1Hz, 3H), 4.06(t, J ═ 11.7Hz, 1H), 2.25-2.10(m, 1H), 2.05(dt, J ═ 9.6, 5.0Hz, dd4H), 1.93 (dt, J ═ 16.2, 7.1Hz, 1H), 1.82(d, J ═ 12.4, 1H), 1.76-1.68 (s, 1H), 1.84 (t, 1H), 1.15.84 (d, J ═ 12.4, 1H), 1H), 1H (d, 1.82 (m, 1H), 1H, 1.84 (d, 1H), 1H, 1. ESI-MS M/z calculated 607.2189, Experimental 608.2 (M +1) ⁺(ii) a Retention time: 2.07min (LC method E.) the second enantiomer to be eluted was 20, 20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (enantiomer 2) (compound 119) (17.84mg, 63%). ESI-MS M/z calculated 607.2189, Experimental 608.3(M +1)⁺(ii) a Retention time: 2.07min (LC method E).

Example 148: preparation of 21, 21-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ] -]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaene-8, 10, 10-trione (compound 122)

Step 1: 2, 2-dimethyl-4- [4- (4-sulfamoylpyrazol-1-yl) butyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

Tert-butyl 2, 2-dimethyl-4- (4-methylsulfonyloxybutyl) pyrrolidine-1-carboxylate (600mg, 1.717mmol), 1H-pyrazole-4-sulfonamide (256mg, 1.740mmol) and potassium carbonate (850mg, 6.150 mmol) were combined in N, N-dimethylformamide (15mL) and stirred at 50 ℃ in a sealed 150mL vessel for 22H, the mixture was cooled to room temperature, poured into water (100mL) and extracted with ethyl acetate (2 × 100mL), the organic layers combined, washed with water (2 × 100mL), dried (sodium sulfate), filtered and concentrated. The orange residue was purified by silica gel chromatography using a gradient of 100% dichloromethane to 15% methanol/dichloromethane to give 2, 2-dimethyl-4- [4- (4-sulfamoylpyrazol-1-yl) butyl as a colorless oil ]Pyrrolidine-1-carboxylic acid tert-butyl ester (499mg, 73%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)8.19(s, 1H), 7.71(s, 1H), 7.23(s, 2H), 4.13(t, J ═ 7.0Hz, 2H), 3.52(dd, J ═ 13.9, 8.6Hz, 1H), 2.06(d, J ═ 12.0 Hz, 1H), 1.85(dd, J ═ 16.8, 10.1Hz, 1H), 1.80-1.71(M, 2H), 1.42-1.34(M, 13H), 1.32(d, J ═ 7.2Hz, 3H), 1.29(d, J ═ 5.6Hz, 1H), 1.23(s, 4H), ESI-MS M/z calculated value 400.21442, experimental value 401.2(M +1)⁺(ii) a Retention time: 1.61min (LC method E).

Step 2: 4- [4- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] pyrazol-1-yl ] butyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (410mg, 1.091mmol) and carbonyldiimidazole (177mg, 1.092mmol) were combined in tetrahydrofuran (6.0mL) and stirred at 50 ℃ for 90min, then 2, 2-dimethyl-4- [4- (4-sulfamoylpyrazol-1-yl) butyl ] was added]Pyrrolidine-1-carboxylic acid tert-butyl ester (257mg, 0.6416 mmol)) Followed by the addition of 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene (240 μ L, 1.605mmol) and the reaction heated at 50 ℃ for 16 h.the reaction was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate followed by brine the organics were separated, dried over sodium sulfate, filtered and evaporated and then purified by silica gel chromatography using a gradient of 100% dichloromethane to 10% methanol/dichloromethane to give 4- [4- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] as an off-white solid ]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Pyrazol-1-yl]Butyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (345mg, 71%). ESI-MS calculated M/z 757.2636, Experimental 758.2 (M +1)⁺(ii) a Retention time: 1.93min (LC method E).

And step 3: 21, 21-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaene-8, 10, 10-trione (compound 122)

4- [4- [4- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] group]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Pyrazol-1-yl]Butyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (315mg, 0.4154 mmol) was dissolved in dichloromethane (8.5mL) and hydrochloric acid (3.25mL, 4M in dioxane, 13.00mmol) was added to the mixture and the mixture was stirred at room temperature for 30 min. The mixture was concentrated to dryness under reduced pressure, redissolved in ethyl acetate and then added with 2M aqueous sodium carbonate (5mL) to bring the pH to about 10 the solution was extracted with ethyl acetate (2 × 10mL), washed with brine, then dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure the resulting material was combined with potassium carbonate (290mg, 2.098mmol), cesium fluoride (95mg, 0.6254mmol),

Molecular sieves and dimethylsulfoxide (10.0mL) were combined in a vial, purged with nitrogen,capping, heating to 155 ℃, and stirring for 20 h. The organics were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% dichloromethane to 10% methanol/dichloromethane, followed by a second column using a gradient of 100% hexane to 80% ethyl acetate/hexane to give 21, 21-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaen-8, 10, 10-trione (compound 122) (131mg, 50%).¹H NMR (400MHz, dimethylsulfoxide-d)₆) 12.34(s, 1H), 8.83(s, 1H), 8.21(d, J ═ 2.7Hz, 1H), 7.94(s, 1H), 7.81(d, J ═ 8.4Hz, 1H), 6.91(d, J ═ 8.2Hz, 1H), 6.12(d, J ═ 2.6Hz, 1H), 4.44(td, J ═ 11.3, 3.3Hz, 1H), 4.31(t, J ═ 7.0Hz, 2H), 4.19(dd, J ═ 19.3, 5.9Hz, 1H), 2.97(t, J ═ 9.5Hz, 1H), 2.33 (dd, J ═ 12.1, 8.3Hz, 1H), 2.08(t, J ═ 6.9, 4.7H, 1H), 8.3, 1H, 7.7H, 8.0 (dd, 7.5H), 7.7H, 7H, 7.0 (d, 3H, 1H), 6.7H, 7H, 7.0 (d, 7H, 7.0, 7H, 6H, 7H, 1H, 7.3H, 1H, 7H, 1H, 6H, 7H, 1H, 7H, 1H, 7H, 1H, 7H, 1H) ESI-MS calculated M/z 621.2345, Experimental 622.3(M +1) ⁺(ii) a Retention time: 2.16min (LC method E).

Example 149: preparation of 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 22-pentaazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (22), 5(10), 6, 8, 20, 23-hexaen-2, 2, 4-trione (compound 123)

Step 1: 2, 2-dimethyl-4- [4- [ (6-sulfamoyl-3-pyridyl) amino ] butyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

In a sealed 5mL vial, a solution of 4- (4-aminobutyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (507mg, 1.875mmol), 5-fluoropyridine-2-sulfonamide (300mg, 1.703mmol) and diisopropylethylamine (1.5mL, 8.612mmol) in n-butanol (3mL) was stirred at 160 ℃ for 16 h. The solvent was removed in vacuo and the residue was dissolved in dichloromethane and washed with water the organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by silica gel chromatography (0% to 40% ethyl acetate/hexanes) to give 2, 2-dimethyl-4- [4- [ (6-sulfamoyl-3-pyridyl) amino]Butyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (210mg, 29%). ESI-MS M/z calculated 426.23007, Experimental 427.26(M +1)⁺(ii) a Retention time: 1.73min (LC method B).

Step 2: 4- [4- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -3-pyridinyl ] amino ] butyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (278mg, 0.7399mmol) and carbonyldiimidazole (120mg, 0.7401mmol) were combined in tetrahydrofuran (6mL) and stirred at 50 ℃ for 90 min. Subsequently, 2-dimethyl-4- [4- [ [ (6-sulfamoyl-3-pyridyl) amino group is added]Butyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (210mg, 0.4923mmol) and 1, 8-diazabicyclo [5.4.0]A solution of undec-7-ene (190mg, 1.248mmol) in tetrahydrofuran (3 mL). The reaction was heated at 50 ℃ overnight. The reaction was diluted with ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered and evaporated, followed by preparative reverse phase HPLC (C)₁₈Acetonitrile/water + hydrochloric acid modifier) to obtain 4- [4- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] amino acid]Ethoxy radicalBase of]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-3-pyridyl]Amino group]Butyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (264.4mg, 68%). ESI-MS M/z calculated 783.27924, experimental 784.39(M +1) ⁺(ii) a Retention time: 0.91min (LC method A).

And step 3: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 22-pentaazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (22), 5(10), 6, 8, 20, 23-hexaen-2, 2, 4-trione (compound 123)

4- [4- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] group]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-3-pyridyl]Amino group]Butyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (260mg, 0.3315mmol) is dissolved in dichloromethane (5mL) and to this solution hydrochloric acid (2.5mL, 4M in dioxane, 10.00mmol) is added and the resulting mixture is stirred at room temperature for 30min

Molecular sieves (300mg) and dimethyl sulfoxide (3mL) were combined in a 5mL vial, which was purged with nitrogen and stirred at 150 ℃ overnight, the mixture was cooled to room temperature, filtered and purified by preparative reverse phase HPLC (C)₁₈Acetonitrile/water + hydrochloric acid modifier) to obtain 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] amino acid ]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 19, 22-pentaazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (22), 5(10), 6, 8, 20, 23-hexaen-2, 2, 4-trione (compound 123) (8.7mg, 4%). ESI-MS M/z Calculation 647.2502, Experimental value 648.34(M +1)⁺(ii) a Retention time: 2.2min (LC method B).

Example 150: preparation of 21, 21-bisMethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaen-8, 10, 10-trione (enantiomer 1) (compound 134) and 21, 21-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 135)

Step 1: 21, 21-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaen-8, 10, 10-trione (enantiomer 1) (compound 134) and 21, 21-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 135)

To racemic 21, 21-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosane-2, 4, 6, 11(23), 12-pentaene-8, 10, 10-trione (100mg, 0.1592mmol) was subjected to chiral SFC chromatography (ChiralPak AS-H (250 × 10mm), 5 μ M column; mobile phase 34% acetonitrile/methanol (90: 10, no modifier), 66% carbon dioxide, 10 mL/min; concentration 24mg/mL in acetonitrile/methanol/dimethyl sulfoxide (80: 10; no modifier), injection volume 70 μ L, 100 bar). The first enantiomer to be eluted is21, 21-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaen-8, 10, 10-trione (enantiomer 1) (compound 134) (24.1mg, 49%). ESI-MS M/z calculated 621.2345, Experimental 622.3(M +1) ⁺(ii) a Retention time: 2.16min (LC method E.) the second enantiomer to be eluted was 21, 21-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 135) (25.4mg, 51%). ESI-MS M/z calculated 621.2345, Experimental 622.3(M +1)⁺(ii) a Retention time: 2.16min (LC method E).

Example 151: preparation of 12, 12, 18-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 138) and 12, 12, 18-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 139)

Step 1: 12, 12, 18-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 138) and 12, 12, 18-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-a sulfur-3-group of compounds,9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 139)

Racemic 12, 12, 18-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl-8- [ 10- (trifluoromethyl)) was chromatographed by SFC using a Phenomenex LUX-4(250 × 10mm) column, 5 μm particle size and 22% methanol (0.1% trifluoroacetic acid), 78% carbon dioxide mobile phase (10mL/min over 6.0min) (injection volume ═ 70 μ L, ca. 24mg/mL in methanol: dimethyl sulfoxide (85: 15))]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]The tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (29mg) was subjected to chiral separation to give 12, 12, 18-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl-2- [1- (trifluoromethyl) methyl ] l-propyl ] e as the first enantiomer to be eluted ]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 1) (compound 138) (7.1mg, 49%); ESI-MS M/z calculated 647.2502, Experimental 648.34 (M +1)⁺(ii) a Retention time: 2.38min (LC method B), and 12, 12, 18-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as the second enantiomer to be eluted]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (enantiomer 2) (compound 139) (9.4mg, 55%); ESI-MS M/z calculated 647.2502, Experimental 648.42(M +1)⁺(ii) a Retention time: 2.38min (LC method B).

Example 152: preparation of 12, 12, 18-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 20-pentaazatetracyclo [17.2.2.111, 14.05, 10]Tetracos-1 (22), 5, 7, 9, 19(23), 20-hexaen-22, 4-triones (Compound 140)

Step 1: 2, 2-dimethyl-4- [3- [ methyl- (5-sulfamoyl-2-pyridyl) amino ] propyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

To the solution is charged with 2, 2-dimethyl-4- [3- (methylamino) propyl group]A20 mL vial of pyrrolidine-1-carboxylic acid tert-butyl ester (350mg, 1.294 mmol) was charged with 6-chloropyridine-3-sulfonamide (261mg, 1.355mmol), potassium carbonate (256 mg, 1.852mmol), and dimethyl sulfoxide (4 mL). The headspace was purged with nitrogen, the vial was capped, and the reaction mixture was stirred at 120 ℃ for 18 h. Cooled to room temperature, diluted with ethyl acetate (about 40mL) and the crude mixture washed with water (10mL), brine (5mL) and the organic layer dried over sodium sulfate, filtered and concentrated in vacuo column chromatography (silica, a gentle gradient of 100% hexane to 100% ethyl acetate) afforded 2, 2-dimethyl-4- [3- [ methyl- (5-sulfamoyl-2-pyridyl) amino as an off-white solid]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (109mg, 20%). ESI-MS M/z calculated 426.23007, Experimental 427.2(M +1)⁺(ii) a Retention time: 1.49min (LC method B).

Step 2: 4- [3- [ [5- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] -methyl-amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To the solution containing 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl group]Ethoxy radical ]Pyrazol-1-yl]A20 mL vial of pyridine-3-carboxylic acid (106 mg, 0.2821mmol) was charged with carbonyldiimidazole (47mg, 0.2899mmol) and tetrahydrofuran (2mL)The reaction mixture was stirred for 2h at which time 2, 2-dimethyl-4- [3- [ methyl- (5-sulfamoyl-2-pyridyl) amino group was added]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (109 mg, 0.2555mmol) in tetrahydrofuran (2mL) followed by the addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (60. mu.L, 0.4012 mmol). The reaction mixture was stirred at room temperature for 18h and quenched with water (about 4mL), aqueous citric acid (about 4mL, 1M) was added and the crude mixture was extracted with ethyl acetate (3 × 10mL), the combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo, column chromatography (silica, gradient of 100% hexane to 100% ethyl acetate) afforded 4- [3- [ [5- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] as an off-white solid]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]-methyl-amino]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (87mg, 43%). ESI-MS M/z calculated 783.27924, Experimental 784.4(M +1)⁺(ii) a Retention time: 2.42min (LC method B).

And step 3: 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-3-yl) propyl-methyl-amino ] -3-pyridinyl ] sulfonyl ] -6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide

To the reaction vessel is charged with 4- [3- [ [5- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] group]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]-methyl-amino]Propyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (87mg, 0.1109mmol) in a vial was added dichloromethane (5mL) followed by dioxane containing hydrochloric acid (1mL, 4M, 4.000mmol) the vial was sealed and the reaction mixture was stirred at room temperature for 2h the solvent was removed in vacuo to give crude 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-3-yl) propyl-methyl-amino as a pale yellow solid]-3-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (75mg, 99%) used without further purification ESI-MS calculated M/z 683.2268, Experimental 684.1(M +1)⁺(ii) a Retention time: 1.61min (LC method B).

And 4, step 4: 12, 12, 18-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 20-pentaazatetracyclo [17.2.2.111, 14.05, 10 ]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 140)

A vial equipped with a stir bar was charged with potassium carbonate (140mg, 1.013mmol) and CsF (131mg, 0.8624 mmol). Addition of 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-3-yl) propyl-methyl-amino]-3-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]A solution of pyridine-3-carboxamide (70 mg, 0.1023mmol) in dimethylsulfoxide (10mL), the vial was sealed, and the reaction mixture was stirred at 200 ℃ in a microwave reactor for 1.5h after cooling to room temperature, the solid was filtered off with ethyl acetate eluent, the filtrate was diluted with ethyl acetate (about 60mL), washed with 1.0M aqueous citric acid (10mL) and brine (5mL), and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Column chromatography (silica, gradient of 0% to 5% methanol/dichloromethane) gave 12, 12, 18-trimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl-l-propyl ] -as an off-white solid]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 20-pentaazatetracyclo [17.2.2.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 140) (9mg, 12%). ESI-MS M/z calculated 647.2502, Experimental 648.2(M +1) ⁺(ii) a Retention time: 2.21min (LC method B).

Example 153: preparation of 4- [3- (3, 3-Dicyclopropylpropoxy) -1H-pyrazol-1-yl]-20, 20-dimethyl-10. lambda.⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (compound 141)

2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (107.6mg, 0.2975mmol) and carbonyldiimidazole (57.89mg, 0.3570mmol) were combined in tetrahydrofuran (2mL) and stirred at 50 ℃ for 90min, then 2, 2-dimethyl-4- [3- (3-sulfamoylpyrazol-1-yl) propyl ] was added]Pyrrolidine-1-carboxylic acid tert-butyl ester (115mg, 0.2975mmol) was added followed by 1, 8-diazabicyclo [5.4.0]Undec-7-ene (67.94mg, 66.74 μ L, 0.4463mmol) and the reaction stirred at room temperature for 18h, the reaction was diluted with ethyl acetate and washed with a saturated solution of ammonium chloride followed by brine the organics were separated, dried over sodium sulfate, filtered and evaporated followed by purification by silica gel chromatography using a gradient of 100% hexane to 100% ethyl acetate to give 4- [3- [3- [ [ 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl as a white solid ]Pyridine-3-carbonyl]Sulfamoyl radical]Pyrazol-1-yl]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (145mg, 67%).¹H NMR (400MHz, chloroform-d) 9.75(s, 1H), 8.30(d, J ═ 2.9Hz, 1H), 8.27-8.20(m, 1H), 7.75(d, J ═ 8.4Hz, 1H), 7.48(t, J ═ 3.1Hz, 1H), 7.05(d, J ═ 2.5Hz, 1H), 5.97(d, J ═ 2.9Hz, 1H), 4.43(t, J ═ 6.8Hz, 2H), 4.20(t, J ═ 7.0Hz, 2H), 3.64(dt, J ═ 42.1, 9.1Hz, 1H), 2.91-2.75(m, 1H), 2.07(s, 1H), 1.97(q, J ═ 6.8, 1H), 9.1Hz, 1H), 2.91-2.75(m, 1H), 2.07(s, 1H), 1.97(q, J ═ 6.8, 1H), 7.8, 7.6, 7.5H), 7.6H, 1H), 7.7, 1H, 7, 1H, 7.6, 7, 7.6, 1H, 7, 5 (J ═ 7, 1H), 0.50-0.38 (M, 4H), 0.32(tt, J ═ 9.0, 6.8Hz, 1H), 0.20(dtd, J ═ 9.5, 4.9, 3.6Hz, 2H), 0.14-0.06 (M, 2H), ESI-MS M/z calculated 729.30756, experimental 730.37(M +1)⁺(ii) a Retention time: 0.91min (LC method A).

Step 2: 4- [3- (3, 3-Dicyclopropylpropoxy) -1H-pyrazol-1-yl]-20, 20-dimethyl-10. lambda.⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (compound 141)

4- [3- [3- [ [ 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl ] is reacted at room temperature]Pyridine-3-carbonyl]Sulfamoyl radical]Pyrazol-1-yl]Propyl radical]A solution of tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (145mg, 0.1985mmol) in dichloromethane (1mL) and trifluoroacetic acid (150. mu.L, 1.960mmol) was stirred for 4 h. The solvent was removed and the residue was dissolved in ethyl acetate. Washed with 2mL of a saturated solution of sodium bicarbonate and the organic layer was collected and the solvent was removed, followed by drying the residue in vacuo. The above residue was dissolved in dimethyl sulfoxide (3mL) and added

Molecular sieves and stir the reaction mixture for 10 min. Subsequently, cesium fluoride (94mg, 0.6188mmol) and potassium carbonate (86mg, 0.6223mmol) were added and the reaction mixture was heated at 150 ℃ overnight the reaction mixture was filtered through a Whatman filter disc (puradisc 25TF) and the filtrate was purified by reverse phase HPLC-MS method using a double gradient run of 50% -99% mobile phase B over 15.0min (mobile phase a ═ water (0.05% hydrochloric acid), mobile phase B ═ acetonitrile) to give 4- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl as a white solid]-20, 20-dimethyl-10. lambda.⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7 ]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (compound 141) (26mg, 22%).¹H NMR (400MHz, chloroform-d) 8.62(s, 1H), 8.17(d, J ═ 2.8Hz, 1H), 7.67(d, J ═ 8.2Hz, 1H), 7.48(d, J ═ 2.3Hz, 1H), 7.07(d, J ═ 2.3Hz, 1H), 7.02(d, J ═ 8.3Hz, 1H), 5.87(d, J ═ 2.8Hz, 1H), 4.41 ═ 4.8 (H), (t, J ═ 6.8Hz, 2H), 4.35(dt, J ═ 13.3, 3.4Hz, 1H), 4.00-3.87(M, 1H), 2.75(t, J ═ 8.2Hz, 1H), 2.25-1.87(M, 3H), 1.80-1.71(M, 1H), 1.62(s, 4H), 1.59(s, 3H), 1.55(s, 3H), 1.47(t, J ═ 12.3Hz, 1H), 0.80(dd, J ═ 12.5, 6.7Hz, 1H), 0.73-0.60(M, 2H), 0.52-0.38(M, 4H), 0.38-0.28(M, 1H), 0.24-0.15(M, 2H), 0.11(dd, 8, 6.8, 7H), 5(M, 2H), 0.8, 2H), 2.3, 2 z + 1H), calculated values of M, 2 z, 2H, 2M, 2H, 3, 2M, 3/3H, 3 z, 3H, 3M, 3H, 3M⁺(ii) a Retention time: 1.82min (LC method G).

Example 154: preparation of 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 21-tetraazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (compound 142)

Step 1: 2, 2-dimethyl-4- (4-oxobutyl) pyrrolidine-1-carboxylic acid tert-butyl ester

Des-Martin periodinane (9.59g, 22.61mmol) was added to 4- (4-hydroxybutyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (5.2g, 19.16mmol) in anhydrous CH at 0 deg.C (ice-water bath) under nitrogen₂Cl₂(35 mL) in a stirred solution. After 15min, the reaction was allowed to warm to ambient temperature and stirring was continued for an additional 3 h-the reaction was diluted with ether (200mL) and a saturated aqueous solution of sodium bicarbonate (100mL) was added slowly (to slow carbon dioxide evolution) — followed by addition of 10% sodium thiosulfate (50mL) and stirring of the mixture at ambient temperature for 30 min-the layers did not separate significantly, whereupon the mixture was filtered through a sintered filter funnel. The layers were separated from the filtrate and the aqueous layer was extracted with ether (2X 100 mL.) the combined organics were washed with brine (100mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude materialThe crude material was purified by silica gel chromatography (gradient of 5% -40% ethyl acetate/hexane) to give the desired tert-butyl 2, 2-dimethyl-4- (4-oxobutyl) pyrrolidine-1-carboxylate (4.39g, 85%) as a clear viscous material.¹H NMR (400MHz, methanol-d)₄)4.48 (t, J ═ 5.5Hz, 1H), 3.64(H, J ═ 4.8Hz, 1H), 2.86(td, J ═ 10.6, 5.2Hz, 1H), 2.30(t, J ═ 7.3Hz, 1H), 2.22-2.06(m, 1H), 1.95(ddt, J ═ 17.2, 11.6, 5.8Hz, 1H), 1.67-1.53 (m, 2H), 1.53-1.48(m, 2H), 1.47(s, 4H), 1.43(s, 5H), 1.40(s, 3H), 1.39-1.34(m, 2H), 1.31(s, 3H). ESI-MS M/z calculated 269.1991, Experimental 270.2(M +1) ⁺(ii) a Retention time: 1.7min (LC method B).

Step 2: 2, 2-dimethyl-4-pent-4-ynyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred solution of tert-butyl 2, 2-dimethyl-4- (4-oxobutyl) pyrrolidine-1-carboxylate (3.0g, 11.14mmol) in dry methanol (40mL) was added potassium carbonate (3.39g, 24.53mmol) at 0 deg.C (ice water bath), followed by dropwise addition of 1-diazo-1-dimethoxyphosphoryl-propan-2-one (2.1mL, 13.99 mmol). After the addition was complete, the mixture was allowed to warm to room temperature and stirred for a total of 16h (the reaction was complete within 4 h). The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate (50mL) and washed with brine (20 mL). The aqueous layer was back-extracted with ethyl acetate (2 × 20mL), and the organic layers were combined, washed with brine (20mL), dried (over anhydrous sodium sulfate), filtered, and concentrated to a clear oil that was purified by silica gel chromatography (gradient of 0% to 20% ethyl acetate/hexanes) to give the desired tert-butyl 2, 2-dimethyl-4-pent-4-ynyl-pyrrolidine-1-carboxylate (2.29g, 77%) as a clear oil.¹H NMR (400MHz, methanol-d)₄)3.72-3.57(m, 1H), 2.86(t, J ═ 10.7Hz, 1H), 2.27-2.07(m, 4H), 1.95(ddd, J ═ 16.7, 12.2, 6.1Hz, 1H), 1.58-1.48(m, 4H), 1.47(s, 5H), 1.43(s, 5H), 1.41(s, 2H), 1.31(s, 3H). ESI-MS m/z calculated value 265.2042, true (m, 1H) and true (ESI-MS m/z) calculated values Test value 266.2(M +1)⁺(ii) a Retention time: 1.77min (LC method B).

And step 3: 2, 2-dimethyl-4- [5- (5-sulfamoyl-2-pyridyl) pent-4-ynyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

A dry 20mL vial was charged with tert-butyl 2, 2-dimethyl-4-pent-4-ynyl-pyrrolidine-1-carboxylate (700mg, 2.638mmol), 6-chloropyridine-3-sulfonamide (900mg, 4.672mmol), cuprous iodide (51 mg, 0.2678mmol), bis (triphenylphosphine) palladium chloride (112mg, 0.1596mmol), and dry N, N-dimethylformamide (6mL) in that order, followed by bubbling nitrogen through the stirred dark mixture for 3min, and diisopropylamine (700. mu.L, 4.995mmol) was added and the vial capped under nitrogen. The reaction was stirred at 52 ℃ for 11 h, then cooled to ambient temperature and poured into water (100mL) and extracted with ethyl acetate (3X 50 mL.) the combined organics were washed successively with water (2X 50mL) and brine (30mL), dried (over anhydrous sodium sulfate), filtered and concentrated under reduced pressure to an orange oil which was purified by silica gel chromatography using a gradient of 15% to 50% ethyl acetate/hexane to give the desired 2, 2-dimethyl-4- [5- (5-sulfamoyl-2-pyridyl) pent-4-ynyl as a white solid ]Pyrrolidine-1-carboxylic acid tert-butyl ester (699mg, 63%).¹H NMR (400MHz, methanol-d)₄)8.91(dd, J ═ 2.4, 0.9Hz, 1H), 8.20(dd, J ═ 8.3, 2.4Hz, 1H), 7.60(dd, J ═ 8.2, 0.9Hz, 1H), 3.71-3.63(m, 1H), 2.90(t, J ═ 10.7Hz, 1H), 2.53(t, J ═ 6.8Hz, 2H), 2.28-2.14(m, 1H), 2.03-1.92(m, 1H), 1.74-1.62(m, 2H), 1.62-1.50(m, 3H), 1.47(s, 5H), 1.43(s, 5H), 1.42(s, 2H), 1.32(s, 3H). ESI-MS M/z calculated 421.20352, Experimental 422.3(M +1)⁺(ii) a Retention time: 1.74min (LC method B).

And 4, step 4: 2, 2-dimethyl-4- [5- (5-sulfamoyl-2-pyridyl) pentyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

Nitrogen was bubbled through 2, 2-dimethyl-4- [5- (5-sulfamoyl-2-pyridyl) pent-4-ynyl]A stirred solution of pyrrolidine-1-carboxylic acid tert-butyl ester (698mg, 1.656mmol) in ethanol (20mL) platinum oxide (76mg, 0.3347mmol) was then added under nitrogen and the reaction stirred at ambient temperature under hydrogen (balloon). After 2h, more platinum oxide (110mg, 0.4844mmol) was added and the reaction stirred for an additional 3 h. The reaction was then purged with nitrogen, 5g of celite was added and stirred for 20min the heterogeneous mixture was filtered through a pad of celite the filtrate was concentrated under reduced pressure to give the crude material which was purified by silica gel chromatography (gradient of 5% -50% ethyl acetate/hexane) to give 2, 2-dimethyl-4- [5- (5-sulfamoyl-2-pyridyl) pentyl ] as a white solid ]Pyrrolidine-1-carboxylic acid tert-butyl ester (655mg, 93%).¹H NMR (400MHz, methanol-d)₄)8.90(dd, J ═ 2.4, 0.8Hz, 1H), 8.17(dd, J ═ 8.2, 2.4Hz, 1H), 7.47(dd, J ═ 8.2, 0.8Hz, 1H), 3.66-3.58 (M, 1H), 2.91-2.80(M, 3H), 2.19-2.05(M, 1H), 1.98-1.86(M, 1H), 1.75(p, J ═ 7.4 Hz, 2H), 1.47(s, 5H), 1.43(s, 4H), 1.42(s, 2H), 1.40(s, 2H), 1.36(s, 6H), 1.30(s, 3H), ESI-MS M/z calculated value 425.23483, experimental value 426.3(M + 1H)⁺(ii) a Retention time: 1.73min (LC method B).

And 5: 4- [5- [5- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] pentyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

Addition of 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] at ambient temperature under nitrogen]Ethoxy radical]Pyrazol-1-yl]To a solution of pyridine-3-carboxylic acid (440mg, 1.171mmol) in anhydrous tetrahydrofuran (6mL) was added carbonyldiimidazole (195mg, 1.203mmol) and the mixture was stirred at this degree of mixing for 3h to form the active acid. Adding 2, 2-dimethyl-4- [5- (5-sulfamoyl) group to active acid solution-2-pyridyl) pentyl group]A solution of pyrrolidine-1-carboxylic acid tert-butyl ester (500mg, 1.175mmol) in anhydrous tetrahydrofuran (4mL) was then added 1, 8-diazabicyclo [5.4.0 ]Undec-7-ene (400. mu.L, 2.675mmol) and the mixture was stirred at ambient temperature for 15 h. The volatiles were removed under reduced pressure and the thick residue was partitioned between water (15mL) and ethyl acetate (30 mL). The mixture was acidified to a pH of about 3-4 with 4M aqueous hydrochloric acid and the layers were separated, the organic phase was washed with brine (20mL) and the combined aqueous layers were re-extracted with ethyl acetate (30 mL). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude material the crude product was chromatographed (silica gel column, eluting with a gradient of 0% to 80% ethyl acetate/hexane) to give 4- [5- [5- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] propane as a white foam]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Pentyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (750mg, 82%).¹H NMR (400MHz, methanol-d)₄)9.02(dd, J ═ 2.3, 0.8Hz, 1H), 8.69(s, 1H), 8.32(d, J ═ 1.0Hz, 1H), 8.32-8.29(m, 1H), 7.98 (d, J ═ 8.3Hz, 1H), 7.65(d, J ═ 8.2Hz, 1H), 7.49(d, J ═ 1.3Hz, 1H), 7.45(dd, J ═ 8.2, 0.8Hz, 1H), 5.97(d, J ═ 2.8Hz, 1H), 4.43-4.33(m, 2H), 3.67-3.56(m, 1H), 2.86(t, J ═ 7.7Hz, 2H), 2.83(d, J ═ 11.1, 1H), 10.7 (t, 10.42H), 6.42 (t, 1H), 1H), 6.6.6H, 1H, 6H, 1H, 6H, 13H, 6H, 1H, 6H, 1H, 6H, 1, 3H) 1.03-0.96(M, 2H), 0.82(tt, J ═ 5.4, 2.9Hz, 2H), ESI-MS M/z calculated 782.284, experimental 783.4(M +1) ⁺(ii) a Retention time: 2.42min (LC method B).

Step 6: 2-chloro-N- [ [6- [5- (5, 5-dimethylpyrrolidin-3-yl) pentyl ] -3-pyridinyl ] sulfonyl ] -6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide (dihydrochloride)

Under nitrogen at 0 deg.C (ice water)Bath) to 4- [5- [5- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] n]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Pentyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (750mg, 0.9575mmol) in anhydrous CH₂Cl₂To the solution in (15mL) was added hydrochloric acid (6.0 mL, 4.0M in dioxane, 24.00 mmol). After 5min, the bath was removed and stirring was continued at room temperature for another 20 min. The reaction was concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (30mL) and the pH was adjusted to about 5 by the addition of saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous portion re-extracted with ethyl acetate (2X 20 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give 2-chloro-N- [ [6- [5- (5, 5-dimethylpyrrolidin-3-yl) pentyl ] as a white solid]-3-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (dihydrochloride) (720mg, 99%). ESI-MS M/z calculated 682.23157, Experimental 683.4 (M +1)⁺(ii) a Retention time: 1.65min (LC method B).

And 7: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 21-tetraazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (compound 142)

Into a 20mL vial was charged 2-chloro-N- [ [6- [5- (5, 5-dimethylpyrrolidin-3-yl) pentyl ] group]-3-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (dihydrochloride) (715mg, 0.9456mmol), potassium carbonate (650mg, 4.703mmol), cesium fluoride (215mg, 1.415mmol) and anhydrous dimethyl sulfoxide (15 mL.) the vial was purged with nitrogen for 2min, capped and stirred at 165 ℃ for 24hThe aqueous layer was extracted with ethyl acetate (50 mL). The combined organics were washed with brine (30mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The crude material was purified by silica gel chromatography (gradient of 0% -55% ethyl acetate/hexane) followed by a second silica gel column (0% -10% methanol/dichloromethane) to provide 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid ]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 21-tetraazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (compound 142) (221mg, 36%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.56(s, 1H), 9.02(s, 1H), 8.31(s, 1H), 8.20(d, J ═ 2.8Hz, 1H), 7.93(d, J ═ 8.2Hz, 1H), 7.63(d, J ═ 8.2Hz, 1H), 6.95(d, J ═ 8.3Hz, 1H), 6.12(d, J ═ 2.7Hz, 1H), 4.32(t, J ═ 7.0Hz, 2H), 3.08-2.93 (m, 1H), 2.91-2.78(m, 1H), 2.49-2.41(m, 1H), 2.08(t, J ═ 7.0Hz, 2H), 2.02-1.87 (m, 3H), 1.85-1.66(m, 2H), 1.55(s, 1H), 4.55 (s, 1H), 4.85 (s, 1H), 4.85-2.85 (s, 1H), 1H, 4.8 (m, 1H), 4.8H, 1H, 4H, 1H, 4H, 1H, 2H, 4H, 2H, 1H) -0.31(s, 1H). ESI-MS M/z calculated 646.2549, Experimental 647.5(M +1)⁺(ii) a Retention time: 1.94min (LC method B).

Example 155: preparation of 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 22-tetraazatetracyclo [18.2.2.111, 14.05, 10]Pentacosane-1 (23), 5, 7, 9, 20(24), 21-hexaene-4, 2, 4-trione (compound 143)

Step 1: 2, 2-dimethyl-4- [5- (6-sulfamoyl-3-pyridyl) pent-4-ynyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

A dry 20mL vial was charged with, in order, 2-dimethyl-4-pent-4-ynyl-pyrrolidine-1-carboxylic acid tert-butyl ester (600mg, 2.261mmol), 5-bromopyridine-2-sulfonamide (640mg, 2.700mmol), copper (I) iodide (44 mg, 0.2310mmol), bis (triphenylphosphine) palladium (II) dichloride (96mg, 0.1368mmol), and dry N, N-dimethylformamide (6 mL). Nitrogen was then bubbled through the stirred dark mixture for 3min and diisopropylamine (450 μ L, 3.211mmol) was added and the vial was capped under nitrogen. The reaction was stirred at 52 ℃ for 12 h, then cooled to ambient temperature and poured into water (80mL) and extracted with ethyl acetate (3X 50 mL). The combined organics were washed successively with water (2 × 50mL) and brine (30mL), dried (over anhydrous sodium sulfate), filtered and concentrated under reduced pressure to an orange oil which was purified by silica gel chromatography using a gradient of 15% to 50% ethyl acetate/hexane to give the desired 2, 2-dimethyl-4- [5- (6-sulfamoyl-3-pyridyl) pent-4-ynyl as a white solid]Pyrrolidine-1-carboxylic acid tert-butyl ester (889mg, 93%). ESI-MS M/z calculated 421.20352, Experimental 422.3(M +1) ⁺(ii) a Retention time: 0.72min (LC method A).

Step 2: 2, 2-dimethyl-4- [5- (6-sulfamoyl-3-pyridyl) pentyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

Bubbling nitrogen through 2, 2-dimethyl-4- [5- (6-sulfamoyl-3-pyridyl) pent-4-ynyl]A stirred solution of pyrrolidine-1-carboxylic acid tert-butyl ester (883mg, 2.095mmol) in ethanol (20mL) platinum (IV) oxide (240mg, 1.057mmol) was then added under nitrogen and the reaction stirred under hydrogen (balloon) at ambient temperature after 2.5h stirring the reaction was purged with nitrogen, 5g of celite was added and stirred for 20min the heterogeneous mixture was filtered through a pad of celite. The dark filtrate was concentrated under reduced pressure, and the residue was dissolved in dichloromethane and filtered again through a silica gel pad to remove residual platinum black material. After concentration under reduced pressure, the crude material was purified by silica gel chromatography (5% -50% ethyl acetate/hexane) to give the desired form2, 2-dimethyl-4- [5- (6-sulfamoyl-3-pyridyl) pentyl ] as white solid]Pyrrolidine-1-carboxylic acid tert-butyl ester (882mg, 99%). ESI-MS M/z calculated 425.23483, Experimental 426.3(M +1)⁺(ii) a Retention time: 1.67min (LC method B).

And step 3: 4- [5- [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -3-pyridinyl ] pentyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

Addition of 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] at ambient temperature under nitrogen]Ethoxy radical]Pyrazol-1-yl]To a solution of pyridine-3-carboxylic acid (773mg, 2.057mmol) in anhydrous tetrahydrofuran (8mL) was added carbonyldiimidazole (340mg, 2.097 mmol). The mixture was stirred at 45 ℃ for 3h to form the active acid. Adding 2, 2-dimethyl-4- [5- (6-sulfamoyl-3-pyridyl) pentyl group to active acid solution]A solution of pyrrolidine-1-carboxylic acid tert-butyl ester (875mg, 2.056mmol) in anhydrous tetrahydrofuran (3mL) was then added 1, 8-diazabicyclo [5.4.0]Undec-7-ene (650 μ L, 4.347mmol) and the mixture stirred at ambient temperature for 48 h. The volatiles were removed under reduced pressure and the thick residue was partitioned between water (15mL) and ethyl acetate (30mL), the mixture was acidified to a pH of about 3-4 with 4M aqueous hydrochloric acid and the layers were separated, the organic layer phase was washed with brine (20mL) and the combined aqueous layers were re-extracted with ethyl acetate (30mL), the combined organics were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude material. The crude product was chromatographed (silica gel column, eluting with a gradient of 0% to 80% ethyl acetate/hexane) to give 4- [5- [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] as a white foam ]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-3-pyridyl]Pentyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (854mg, 53%). ESI-MS calculated M/z 782.284, Experimental 783.5(M +1)⁺(ii) a Retention time: 2.2min (LC method B).

And 4, step 4: 2-chloro-N- [ [5- [5- (5, 5-dimethylpyrrolidin-3-yl) pentyl ] -2-pyridyl ] sulfonyl ] -6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide (hydrochloride)

To 4- [5- [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] at 0 deg.C (ice-water bath) under nitrogen]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-3-pyridyl]Pentyl radical]After addition of hydrochloric acid in dioxane (6.8mL, 4.0M, 27.20mmol) to a stirred solution of tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (850mg, 1.085mmol) in anhydrous dichloromethane (10mL), 10min, the bath was removed and stirring continued at room temperature for 30min. The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain crude 2-chloro-N- [ [5- [5- (5, 5-dimethylpyrrolidin-3-yl) pentyl ] as a pale yellow foam ]-2-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (hydrochloride) (781 mg, 100%). ESI-MS M/z calculated 682.23157, Experimental 683.4(M +1)⁺(ii) a Retention time: 1.71min (LC method B).

And 5: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 22-tetraazatetracyclo [18.2.2.111, 14.05, 10]Pentacosane-1 (23), 5, 7, 9, 20(24), 21-hexaene-2, 2, 4-trione (compound 143)

Into a 20mL vial was charged 2-chloro-N- [ [5- [5- (5, 5-dimethylpyrrolidin-3-yl) pentyl ] group]-2-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (hydrochloride) (0.812g, 1.128mmol), Potassium carbonate (1.11)g, 8.032mmol), cesium fluoride (0.258g, 1.698mmol) and anhydrous dimethyl sulfoxide (25 mL.) the vial was purged with a stream of nitrogen for 2min, capped and stirred at 165 ℃ for 17 h. the reaction was cooled to ambient temperature and the mixture was diluted with ethyl acetate (30mL) and washed with a saturated aqueous solution of sodium bicarbonate followed by brine. The organics were separated, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. Subsequent silica gel chromatography (gradient of 0% -55% ethyl acetate/hexane) followed by another column of silica gel (0% -10% methanol/dichloromethane) gave 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid ]Ethoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 22-tetraazatetracyclo [18.2.2.111, 14.05, 10]Pentacosac-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (compound 143) (80mg, 11%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.59(s, 1H), 8.69(s, 1H), 8.19 (d, J ═ 2.8Hz, 1H), 8.14(d, J ═ 7.9Hz, 1H), 7.98(d, J ═ 8.1Hz, 1H), 7.91(d, J ═ 8.3Hz, 1H), 6.91(d, J ═ 8.3Hz, 1H), 6.10(d, J ═ 2.7Hz, 1H), 4.32(t, J ═ 7.0Hz, 2H), 3.01-2.87(m, 1H), 2.74-2.62(m, 1H), 2.47-2.36(m, 1H), 2.08(t, J ═ 7.0Hz, 2H), 2.03-1.82(m, 3H), 1.92 (m, 1H), 2.47-2.36(m, 1H), 2.08(t, J ═ 7.0Hz, 2H), 2.03-1H), 2.82 (m, 3H), 1.92 (m, 3.64, 3.53, 3.0H), 3.33 (m, 1H), 3.33 (m, 3.0, 3H), 3.0 (m, 3.0, 1H, 0.82(d, J ═ 12.6Hz, 1H), 0.73-0.59(m, 1H), 0.08-0.03 (m, 1H). ESI-MS M/z calculated 646.2549, Experimental 647.5(M +1)⁺(ii) a Retention time: 1.96min (LC method B).

Example 156: preparation of 13, 20, 20-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7 ]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (compound 144)

Step 1: 1- [ (4-methoxyphenyl) methyl ] -5-methyl-3-nitro-pyrazole

A100 mL round bottom flask attached to a reflux condenser was charged with 1- (bromomethyl) -4-methoxy-benzene (2.7g, 13.43mmol), acetonitrile (20mL), 5-methyl-3-nitro-1H-pyrazole (1.55g, 12.20mmol), and potassium carbonate (2.53g, 18.31 mmol). The mixture was stirred at 80 ℃ for 6h, then at room temperature for more than 3 days, then concentrated under reduced pressure, the residue was suspended in dichloromethane (80mL), after stirring for 10min, the mixture was filtered and the filtrate was mixed with silica gel, then concentrated the residue was purified by silica gel chromatography using a gradient of 0% to 30% ethyl acetate/heptane to obtain 1- [ (4-methoxyphenyl) methyl ] acetate as a yellow solid]-5-methyl-3-nitro-pyrazole (2.4g, 80%).¹H NMR(300MHz，CDCl₃)2.25(s，3H)，3.79(s，3H)，5.28(s， 2H)，6.67(s，1H)，6.87(d，J＝8.7Hz，2H)，7.14(d，J＝8.7Hz，2H)。ESI-MS m/z 270.1(M+Na)⁺(ii) a Retention time: 1.88min (LC method I).

Step 2: 1- [ (4-methoxyphenyl) methyl ] -5-methyl-pyrazol-3-amine

1- [ (4-methoxyphenyl) methyl group at 80 DEG C]-5-methyl-3-nitro-pyrazole (2.4g, 9.707mmol), NH₄A mixture of Cl (5g, 3.268mL, 93.47mmol), iron (5g, 89.53mmol), EtOH (20mL) and water (4 mL) was stirred overnight after cooling to room temperature, the reaction mixture was filtered through a pad of celite, washed with methanol the filtrate was concentrated, and the residue was suspended in water (50mL) and extracted with ethyl acetate (80mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1- [ (4-methoxyphenyl) methyl ] methyl as a red oil ]-5-methyl-pyrazol-3-amine (2g, 91% purity, obtained by LCMS, 86% yield).¹H NMR(300MHz，CDCl₃)2.13(s，3H)，3.78(s，3H)，5.01(s, 2H), 5.44(s, 1H), 6.83(d, J ═ 8.7Hz, 2H), 7.04(d, J ═ 8.7Hz, 2H), ESI-MS M/z calculated 217.1215, experimental 218.2(M +1)⁺(ii) a Retention time: 1.21min (LC method I).

And step 3: 1- [ (4-methoxyphenyl) methyl ] -5-methyl-pyrazole-3-sulfonyl chloride

1- [ (4-methoxyphenyl) methyl group]-5-methyl-pyrazol-3-amine (20g, 92mmol) was dissolved in AcOH (60mL) and formic acid (20mL) the mixture was cooled with a bath of ice and methanol. Hydrochloric acid (15.2mL, 12M, 182mmol) was then added. After the internal temperature reached about-8 ℃, a solution of sodium nitrite (6.6g, 96mmol) in water (10mL) was slowly added, keeping the internal temperature between-5 ℃ and-10 ℃, the mixture was stirred at the same temperature for 5min, then added in portions to CuCl (2.74g, 28mmol), SO, with a pipette at room temperature₂(44g, 343mmol) and AcOH (60mL) (preparation of SO in AcOH by passing gas through AcOH at 0 deg.C₂Solution) the resulting mixture was allowed to warm to room temperature for 1 h. The mixture was concentrated under reduced pressure the residue was mixed with diethyl ether (200mL) and ice water (50 mL). There was a large amount of black oil that was insoluble in either phase after vigorous stirring of the mixture for 20min, the two layers separated. The organic layer was washed with water (2X 50mL), brine (30mL) and concentrated under reduced pressure, and finally co-evaporated with toluene (60mL) to give 1- [ (4-methoxyphenyl) methyl group as a brown oil ]ESI-MS M/z calculated 300.0335, Experimental 323.0(M + Na)⁺(ii) a Retention time: 2.05min (LC method I).

And 4, step 4: 1- [ (4-methoxyphenyl) methyl ] -5-methyl-pyrazole-3-sulfonamide

1- [ (4-methoxyphenyl) methyl group]-5-methyl-pyrazole-3-sulfonyl chlorideAfter addition of a solution of (586mg, 1.9484mmol) in dichloromethane (4mL) to a solution of ammonia (15mL, 0.5M in 1, 4-dioxane, 7.5000mmol) cooled (partially frozen) with ice water 30min, the cooling bath was removed and the reaction stirred at room temperature for 2h, after which it was concentrated under reduced pressure]5-methyl-pyrazole-3-sulfonamide (200mg, 36% yield). ESI-MS M/z calculated 281.0834, Experimental 282.1(M +1)⁺(ii) a Retention time: 1.49min (LC method I).

And 5: 5-methyl-1H-pyrazole-3-sulfonamides

1- [ (4-methoxyphenyl) methyl group was added at 80 deg.C (oil bath)]A solution of-5-methyl-pyrazole-3-sulfonamide (16.3g, 57.9 mmol) in trifluoroacetic acid (80mL) was stirred overnight. The mixture was concentrated and the residue was purified by silica gel chromatography using 0% -100% ethyl acetate/heptane the fractions containing the desired product were combined and concentrated triturating the residue with dichloromethane (30mL) to afford 5-methyl-1H-pyrazole-3-sulfonamide as a light yellow solid (6741mg, 69% yield). ¹H NMR (300MHz, dimethylsulfoxide-d)₆)ppm 2.25(s，3H)，6.32(s， 1H)，7.28(s，2H)，13.11(br.s.，1H)。

Step 6: 2, 2-dimethyl-4- [3- (5-methyl-3-sulfamoyl-pyrazol-1-yl) propyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

Tert-butyl 2, 2-dimethyl-4- (3-methylsulfonyloxypropyl) pyrrolidine-1-carboxylate (1.35g, 4.024 mmol) and 5-methyl-1H-pyrazole-3-sulfonamide (638mg, 3.958mmol) were dissolved in N, N-dimethylformamide (41.32mL), followed by potassium carbonate (1.95g, 14.11mmol), and in a 150mL sealed vessel at 80 ℃ stirred for 20H, cooled, poured into water (100mL), and washed with ethyl acetate(2X 100mL), the organic layers were combined, washed with water (2X 100mL), dried (sodium sulfate), filtered and concentrated the orange residue was purified by silica gel chromatography using a gradient of 100% hexane to 100% ethyl acetate to give a colorless oil which turned to a white solid after drying in vacuo, i.e., 2-dimethyl-4- [3- (5-methyl-3-sulfamoyl-pyrazol-1-yl) propyl ] p]Pyrrolidine-1-carboxylic acid tert-butyl ester (419mg, 52%).¹H NMR (400MHz, dimethylsulfoxide-d)₆) 7.31(s, 2H), 6.36(s, 1H), 4.05(t, J ═ 6.4Hz, 2H), 3.54(dd, J ═ 18.2, 8.1Hz, 1H), 2.77(q, J ═ 10.2Hz, 1H), 2.31(d, J ═ 15.4Hz, 3H), 2.12(d, J ═ 19.6Hz, 1H), 1.87 (td, J ═ 14.0, 6.4Hz, 1H), 1.78-1.65(M, 2H), 1.41-1.28(M, 15H), 1.24(s, 3H), ESI-MS M/z calculated value 400.21442, experimental value 401.2(M +1) ⁺(ii) a Retention time: 1.54min (LC method E).

And 7: 4- [3- [3- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -5-methyl-pyrazol-1-yl ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (485mg, 1.291mmol) and carbonyldiimidazole (210mg, 1.295mmol) were combined in tetrahydrofuran (8.0mL) and stirred at room temperature for 90 min. Subsequently, 2-dimethyl-4- [3- (5-methyl-3-sulfamoyl-pyrazol-1-yl) propyl ] is added]Pyrrolidine-1-carboxylic acid tert-butyl ester (342mg, 0.8539mmol) was added followed by 1, 8-diazabicyclo [5.4.0]Undec-7-ene (325. mu.L, 2.173mmol) and the reaction was heated at 50 ℃ for 16 h. The reaction was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate followed by brine. The organics were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexane to 100% ethyl acetate to give 4- [3- [3- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] propyl ] as an off-white solid]Ethoxy radical]Pyrazol-1-yl]Pyridine-3- Carbonyl radical]Sulfamoyl radical]-5-methyl-pyrazol-1-yl]Propyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (451mg, 70%). ESI-MS M/z calculated 757.2636, Experimental 758.2(M +1)⁺(ii) a Retention time: 2.32min (LC method E).

And 8: 13, 20, 20-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (compound 144)

4- [3- [3- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] group]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-5-methyl-pyrazol-1-yl]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (451mg, 0.5948mmol) was dissolved in dichloromethane (11mL) and to this mixture was added hydrochloric acid (4.5mL, 4M in dioxane, 18.00mmol) and stirred at room temperature for 45min

Molecular sieves and dimethylsulfoxide (13.5mL) were combined in a vial, purged with nitrogen, capped, heated to 155 ℃, and stirred for 20 h. Cooled to room temperature and filtered, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, followed by brine. The organics were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexane to 80% ethyl acetate/hexane to give 13, 20, 20-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9,14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (compound 144) (141mg, 38%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.68(s, 1H), 8.19(d, J ═ 2.8Hz, 1H), 7.70(d, J ═ 8.2Hz, 1H), 6.88 (d, J ═ 8.2Hz, 1H), 6.69(s, 1H), 6.09(d, J ═ 2.7Hz, 1H), 4.30(t, J ═ 7.0Hz, 2H), 4.10-3.94(m, 2H), 2.82-2.71(m, 1H), 2.34(d, J ═ 8.9Hz, 3H), 2.13(dd, J ═ 8.7, 4.0Hz, 1H), 2.09-2.02(m, 3H), 1.96-1.80(m, 3H), 1.77 (ESI, J ═ 11.9, 5.2H, 1H), 1.59 (m, 3H), 1.35-3H, 19 (m, 3H), 3H, 19 (m, 3H, 19, 3H, 19 (z, 3H, 19, 3H, 19(d, 3H, 1.9, m, 1.9, 3H, 1.9, 3H, experimental value 622.2 (M +1) ⁺(ii) a Retention time: 2.14min (LC method E).

Example 157: preparation of 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda⁶-thia-3, 9, 11, 24-tetraazatetracyclo [18.3.1.05, 10.011, 15]Tetracosane-1 (24), 5(10), 6, 8, 20, 22-hexaen-2, 2, 4-trione (compound 147)

Step 1: 2, 2-dimethyl-5- [3- [ (6-sulfamoyl-2-pyridyl) oxy ] propyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

To a 20mL vial was added 5- (3-hydroxypropyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (631 mg, 2.452mmol) and anhydrous N, N-dimethylformamide (8mL), to the solution was added 60% NaH (196mg, 4.900mmol) portionwise (note: gas evolution), and the mixture was stirred at room temperature for 15 min. 6-Fluoropyridine-2-sulfonamide (432mg, 2.452mmol) was then added and the resulting mixture was stirred at room temperature for 30 min. To the stirred solution at room temperature was added NaH (98mg, 2.450mmol) andand the reaction vial was capped. The resulting mixture was stirred at 100 ℃ for 14h, the reaction solution was diluted with ethyl acetate, then poured into 1N aqueous citric acid and extracted with ethyl acetate (2 ×), the combined organic fractions were dried (sodium sulfate), filtered and concentrated to a clear oil which was purified by silica gel chromatography using a mobile phase gradient of 100% hexane to 100% ethyl acetate to give 2, 2-dimethyl-5- [3- [ (6-sulfamoyl-2-pyridyl) oxy ]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (350mg, 35%). ESI-MS M/z calculated 413.19846, Experimental 414.31 (M +1)⁺(ii) a Retention time: 0.69min (LC method A).

Step 2: 5- [3- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] oxy ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (387mg, 1.030mmol) and carbonyldiimidazole (193mg, 1.190mmol) were combined in dry tetrahydrofuran (8mL) and stirred at 50 ℃ for 75min, then 2, 2-dimethyl-5- [3- [ (6-sulfamoyl-2-pyridyl) oxy ] was added]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (328mg, 0.7932mmol) and 1, 8-diazabicyclo [5.4.0]Solution of undec-7-ene (300 μ L, 2.006mmol) in tetrahydrofuran (7 mL.) the reaction was heated at 50 ℃ for 4h, diluted with ethyl acetate and washed with 1M citric acid solution followed by brine. The organics were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexane to 75% ethyl acetate/hexane to give 5- [3- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] 3- [2- (trifluoromethyl) cyclopropyl ] hexane as an off-white solid ]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Oxy radical]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (409mg, 67%). ESI-MS calculated M/z 770.2476, Experimental 771.37(M +1)⁺(ii) a Retention time: 0.92min (LC method A).

And step 3: 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda⁶-thia-3, 9, 11, 24-tetraazatetracyclo [18.3.1.05, 10.011, 15]Tetracosane-1 (24), 5(10), 6, 8, 20, 22-hexaen-2, 2, 4-trione (compound 147)

Reacting 5- [3- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] group]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Oxy radical]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (408mg, 0.5290mmol) was dissolved in dichloromethane (7mL) and to this mixture was added hydrochloric acid (4mL, 4M in dioxane, 16.00mmol) and stirred at room temperature for 30min

Molecular sieves and dimethylsulfoxide (8mL) were combined in a vial, purged with nitrogen, capped, heated to 140 ℃ and stirred for 16h ₁₈Purification on column (30% -99% acetonitrile/water +5mM hydrochloric acid) to give 12, 12-dimethyl-8- (3- {2- [1- (trifluoromethyl) cyclopropyl ] acid as a white solid]Ethoxy } -1H-pyrazol-1-yl) -19-oxa-2. lambda⁶-thia-3, 9, 11, 24-tetraazatetracyclo [18.3.1.05, 10.011, 15]Tetracosane-1 (24), 5(10), 6, 8, 20, 22-hexaen-2, 2, 4-trione (compound 147) (17mg, 5%). ESI-MS M/z calculated 634.2185, Experimental 635.29 (M +1)⁺(ii) a Retention time: 2.0min (LC method B).

Example 158: preparation of 13, 20, 20-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (enantiomer 1) (compound 150) and13, 20, 20-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 2) (Compound 151)

Step 1: 13, 20, 20-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda ⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (enantiomer 1) (compound 150) and 13, 20, 20-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 2) (Compound 151)

To racemic 13, 20, 20-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Dodecan-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (114mg, 0.1815mmol) was subjected to chiral SFC chromatography. The following SFC protocol was employed: ChiralPak AS-H (150X 21.2mm), 5 μm; 35 ℃ mobile phase: 25% acetonitrile: methanol (90: 10; no modifier), 75% carbon dioxide (70mL/min over 8.0min) (injection volume 70 μ L, about 32mg/mL in acetonitrile: methanol (90: 10)) to give 13, 20, 20-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] 4- (3- {2- [1- (trifluoromethyl) cyclopropyl) as a white solid as the first enantiomer to be eluted ]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosate-2, 4, 6, 11(22),12-Pentagen-8, 10, 10-trione (enantiomer 1) (Compound 150) (51.27mg, 91%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.66(s, 1H), 8.19(d, J ═ 2.8Hz, 1H), 7.70(d, J ═ 8.2Hz, 1H), 6.88(d, J ═ 8.2Hz, 1H), 6.69(s, 1H), 6.09(d, J ═ 2.7Hz, 1H), 4.31(t, J ═ 7.0Hz, 2H), 4.10-3.93(M, 2H), 2.85-2.70(M, 1H), 2.35(s, 3H), 2.12(d, J ═ 5.6 Hz, 1H), 2.07(t, J ═ 7.1Hz, 3H), 1.97-1.81(M, 3H), 1.77(dd, J ═ 11.8, 5.4, 1H), 1H (s, 3H), 3H), 1.77(dd, 11.8, 5.8, 3H), 19 (s, 3H), 3H, 89(d, 3H, 9, 15H, M.⁺(ii) a Retention time: 2.19min (LC method E.) the second enantiomer to be eluted was 13, 20, 20-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (enantiomer 2) (compound 151) (31.08mg, 55%). ESI-MS M/z calculated 621.2345, Experimental value 622.5(M +1) ⁺(ii) a Retention time: 2.19min (LC method E).

Example 159: preparation of 21, 21-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ] -]Ethoxy } -1H-pyrazol-1-yl) -18-oxa-10 lambda⁶-thia-1, 3, 9, 14, 15-pentaazatetracyclo [17.2.1.02, 7.011, 15-]Docosac-2 (7), 3, 5, 11, 13-pentaene-8, 10, 10-trione (compound 152)

Step 1: 2, 2-dimethyl-4- [2- (3-sulfamoylpyrazol-1-yl) ethoxy ] pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution containing 4- (2-hydroxyethoxy) -2, 2-dimethyl-pyrazineDichloromethane (70mL) was added to a nitrogen-charged round-bottom flask of tert-butyl pyrrolidine-1-carboxylate (1.94g, 7.480 mmol) and Et was added₃The solution was cooled to 0 ℃ before N (6mL, 43.05 mmol) and methanesulfonyl chloride (1.7mL, 21.96 mmol). the reaction mixture was stirred for 20h, after 1h it was allowed to warm to room temperature (clear solution turned cloudy orange after 10 min). The reaction mixture was quenched by the addition of water. Dichloromethane was added followed by brine, and the organic layer was separated the aqueous layer was further extracted with dichloromethane (2 × 20mL), and the combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting material was dried in vacuo for 1H to give a yellow oil which was combined with 1H-pyrazole-3-sulfonamide (1.1g, 7.475mmol) in a round bottom flask followed by the addition of potassium carbonate (2.23g, 16.14 mmol) and the mixture dissolved in N, N-dimethylformamide (13 mL). The reaction mixture was stirred at 50 ℃ in a 150mL sealed vessel for 48h the mixture was cooled to room temperature, poured into water (100mL) and extracted with ethyl acetate (2 × 100mL), the organic layers were combined, washed with water (2 × 100mL), dried (sodium sulfate), filtered and concentrated the orange residue was purified by silica gel chromatography using a gradient of 100% hexane to 100% ethyl acetate to give 2, 2-dimethyl-4- [2- (5-sulfamoylpyrazol-1-yl) ethoxy ] ethoxy as the first eluting less polar regioisomer ]Pyrrolidine-1-carboxylic acid tert-butyl ester (550mg, 38%). ESI-MS M/z calculated 388.17804, Experimental 389.1(M +1)⁺(ii) a Retention time: 0.56min (LC method A).

Step 2: 4- [2- [3- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] pyrazol-1-yl ] ethoxy ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (183.5 mg, 0.4884mmol) and carbonyldiimidazole (91.40mg, 0.5637mmol) were combined in dry tetrahydrofuran (4 mL) and stirred at 50 ℃ for 90min, then 2, 2-dimethyl-4- [2- (2-methyl-4-hydroxy-ethyl-2-carboxylate) was added3-sulfamoylpyrazol-1-yl) ethoxy]Pyrrolidine-1-carboxylic acid tert-butyl ester (146mg, 0.3758mmol) and 1, 8-diazabicyclo [5.4.0]Solution of undec-7-ene (142.1 μ L, 0.9502mmol) in tetrahydrofuran (7 mL). The reaction was heated at 50 ℃ for 4 h. The organics were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexane to 75% ethyl acetate/hexane to give 4- [2- [3- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] hexane as an off-white solid ]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Pyrazol-1-yl]Ethoxy radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (162mg, 58%). ESI-MS M/z calculated 745.22723, Experimental 746.22(M +1)⁺(ii) a Retention time: 0.87min (LC method A).

And step 3: 21, 21-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -18-oxa-10 lambda⁶-thia-1, 3, 9, 14, 15-pentaazatetracyclo [17.2.1.02, 7.011, 15-]Docosac-2 (7), 3, 5, 11, 13-pentaene-8, 10, 10-trione (compound 152)

4- [2- [3- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] group]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Pyrazol-1-yl]Ethoxy radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (162mg, 0.2171 mmol) was dissolved in dichloromethane (3mL) and to this mixture was added hydrochloric acid (1.6mL, 4M in dioxane, 6.400mmol) and stirred at room temperature for 30min

Molecular sieves and dimethylsulfoxide (3.5mL) were combined in a vial, purged with nitrogen, capped, heated to 140 deg.C, and stirred for 10h ₁₈Purification on column (30% -99% acetonitrile/water +5mM hydrochloric acid) to give 21, 21-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] acid as a white solid]Ethoxy } -1H-pyrazol-1-yl) -18-oxa-10 lambda⁶-thia-1, 3, 9, 14, 15-pentaazatetracyclo [17.2.1.02, 7.011, 15-]Docosac-2 (7), 3, 5, 11, 13-pentaen-8, 10, 10-trione (compound 152) (45 mg, 34%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)13.14(s, 1H), 8.28(d, J ═ 2.8Hz, 1H), 7.96(d, J ═ 8.3Hz, 1H), 7.71(d, J ═ 2.0Hz, 1H), 7.25(d, J ═ 8.2Hz, 1H), 7.05 (d, J ═ 2.0Hz, 1H), 6.14(d, J ═ 2.8Hz, 1H), 4.79-4.63(m, 1H), 4.61-4.46(m, 1H), 4.32(t, J ═ 7.0Hz, 2H), 4.17-3.98(m, 2H), 3.89(ddd, J ═ 11.1, 6.4, 2.7Hz, 1H), 3.39 (ddd, J ═ 11.0, 4.92, 1H), 3.91, 3.92 (ddd, 1H), 3.06H, 3.9, 13.2.7H, 1H, 13.06 (ddh, 1H), 3.2H, 13.2H, 1H, 6.2H, and 1H. ESI-MS M/z calculated 609.1981, Experimental 610.25(M +1)⁺(ii) a Retention time: 2.04min (LC method B).

Example 160: preparation of (14S) -12, 12-dimethyl-8- (2-oxo-3- {2- [1- (trifluoromethyl) cyclopropyl ]Ethoxy } pyrrolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 158)

Step 1: 3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrrolidin-2-one

To 3-bromopyrrolidin-2-one (600mg, 3.659mmol) and 2- [1- (trifluoromethyl) cyclopropyl ] over 2min at 0 deg.C (ice water bath) under nitrogen]To a stirred solution of ethanol (665mg, 4.315mmol) in anhydrous tetrahydrofuran (15mL) was added hexamethyl chloridePotassium bis-silazide (16.0mL, 0.5M in toluene, 8.000 mmol.) the reaction was gradually warmed to ambient temperature overnight (14 h.) the reaction was acidified with glacial acetic acid (300 μ L, 5.275mmol) and the volatiles were removed under reduced pressure at 20 ℃. The organic layer was dried (anhydrous sodium sulfate), filtered and concentrated under reduced pressure to give a light brown crude material which was purified by silica gel chromatography (gradient of 0% to 10% methanol in dichloromethane) to give 3- [2- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Ethoxy radical]Pyrrolidin-2-one (285mg, 33%).¹H NMR (400MHz, benzene-d) ₆)6.76(s, 1H), 4.21(dt, J ═ 9.4, 6.7Hz, 1H), 3.73-3.64(M, 1H), 3.55(t, J ═ 7.3Hz, 1H), 2.67(dddd, J ═ 9.3, 7.6, 4.6, 1.2Hz, 1H), 2.46(dt, J ═ 9.6, 7.1Hz, 1H), 1.95(dt, J ═ 14.3, 7.1Hz, 1H), 1.90-1.81 (M, 1H), 1.74-1.58(M, 2H), 0.86-0.77(M, 2H), 0.54-0.43(M, 2H), ESI-MS M/z calculated value 237.09766, experimental value 238.1(M + 1H)⁺(ii) a Retention time: 0.9min (LC method B).

Step 2: (14S) -12, 12-dimethyl-8- (2-oxo-3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } pyrrolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 158)

(14S) -8-chloro-12, 12-dimethyl-2. lambda. was added to a 5mL vial in order⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (100 mg, 0.2222mmol), 3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrrolidin-2-one (63mg, 0.2656 mmol), cesium carbonate (275mg, 0.8440mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (20 mg, 0.03457mmol) (Xantphos), and anhydrous dioxane (2mL) . Followed by addition of Pd under nitrogen₂(dba)₃(20mg, 0.02184mmol) and nitrogen sparged for a further 2min and capped under nitrogen the mixture was stirred at 115 ℃ for 15h, the mixture was cooled to ambient temperature and neutralized with glacial acetic acid (150 μ L, 2.638mmol), the volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (3.0mL) and filtered through a Whatman 0.45 μm PTFE syringe filter pad, the sample was purified using preparative reverse phase HPLC-MS (30% -99% acetonitrile/water, over 15min (hydrochloric acid as modifier)), the desired product fractions were combined and concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (25mL) and washed successively with saturated aqueous sodium bicarbonate solution (2X 10mL) and brine (10mL), the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (14S) -12 as an off-white solid, 12-dimethyl-8- (2-oxo-3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } pyrrolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 158) (31mg, 19%).¹H NMR (400MHz, methanol-d)₄)7.78(dd, J ═ 8.4, 2.0Hz, 1H), 7.59(dd, J ═ 8.4, 4.4Hz, 1H), 7.53(dd, J ═ 8.5, 7.1Hz, 1H), 7.16 (d, J ═ 7.3Hz, 1H), 6.65(d, J ═ 8.5Hz, 1H), 4.26(dt, J ═ 12.5, 8.0Hz, 1H), 4.22-4.00 (m, 2H), 3.97(dt, J ═ 9.1, 6.8Hz, 1H), 3.92-3.71(m, 2H), 3.29-3.21(m, 1H), 3.03(d, J ═ 13.9Hz, 1H), 2.86(t, J ═ 10.2, 1H), 3.29-3.21(m, 1H), 3.03(d, J ═ 13.9Hz, 1H), 2.86(t, J ═ 10.8, 2H), 3.8H, 1H, 3.8H), 3.8H, 1H, 3.8H, 1H, 8H, 1H, 3.8H, 1H, 3.5 (dd, 8H), 3.8, 1.54(s, 3H), 1.47-1.36(m, 1H), 0.96-0.91(m, 2H), 0.84-0.77(m, 2H). ESI-MS M/z calculated 650.2498, Experimental 651.4 (M +1) ⁺(ii) a Retention time: 2.04min (LC method B).

Example 161: preparation of 20, 20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl [)]Ethoxy } -1H-pyrazol-1-yl) -17-oxa-10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosal-2 (7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione(s) ((s))Compound 164), 20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -17-oxa-10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2 (7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 1) (compound 302) and 20, 20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -17-oxa-10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2 (7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 167)

To a nitrogen-charged round bottom flask containing 4- (2-hydroxyethoxy) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.94g, 7.480 mmol) was added dichloromethane (70 mL). Adding Et ₃The solution was cooled to 0 ℃ before N (6mL, 43.05 mmol) and methanesulfonyl chloride (1.7mL, 21.96 mmol). the reaction mixture was stirred for 20h, after 1h it was allowed to warm to room temperature (clear solution turned cloudy orange after 10 min). The reaction mixture was quenched by addition of water dichloromethane was added followed by addition of brine, and the organic layer was separated the aqueous layer was extracted with additional dichloromethane (2 x 20mL) and the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure the resulting material was dried in vacuo for 1H to give a yellow oil which was combined with 1H-pyrazole-3-sulfonamide (1.1g, 7.475mmol) in a round bottom flask followed by addition of potassium carbonate (2.23g, 16.14 mmol) and the mixture was dissolved in N, N-dimethylformamide (13 mL). The reaction mixture was stirred in a 150mL sealed vessel at 50 ℃ for 48 h. The mixture was cooled to room temperature and poured into water (100)mL) and extracted with ethyl acetate (2 × 100mL), the organic layers were combined, washed with water (2 × 100mL), dried (sodium sulfate), filtered and concentrated an orange residue was purified by silica gel chromatography using a gradient of 100% hexane to 100% ethyl acetate to give 2, 2-dimethyl-4- [2- (3-sulfamoylpyrazol-1-yl) ethoxy ] isomer as the second eluting higher polar regioisomer ]Pyrrolidine-1-carboxylic acid tert-butyl ester (475mg, 33%). ESI-MS M/z calculated 388.17804, Experimental 389.1(M +1)⁺(ii) a Retention time: 0.52min (LC method A).

2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (691.7 mg, 1.841mmol) and carbonyldiimidazole (310.0mg, 1.912mmol) were combined in dry tetrahydrofuran (15 mL) and stirred at 40 ℃ for 60 min. Followed by the addition of 2, 2-dimethyl-4- [2- (3-sulfamoylpyrazol-1-yl) ethoxy]Pyrrolidine-1-carboxylic acid tert-butyl ester (550mg, 1.416mmol) and 1, 8-diazabicyclo [5.4.0]A solution of undec-7-ene (538.9mg, 529.4. mu.L, 3.540mmol) in tetrahydrofuran (7 mL). The reaction was heated at 40 ℃ for 14h, diluted with ethyl acetate and washed with 1M citric acid solution followed by brine the organics were separated, dried over sodium sulfate, filtered and evaporated and then purified by silica gel chromatography using a gradient of 100% hexane to 75% ethyl acetate/hexane to give 4- [2- [3- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] hexane as an off-white solid ]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Pyrazol-1-yl]Ethoxy radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (493mg, 47%). ESI-MS M/z calculated 745.22723, experimental 746.29(M +1)⁺(ii) a Retention time: 0.83min (LC method A).

And step 3: 20, 20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy-1H-pyrazol-1-yl) -17-oxa-10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2 (7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (compound 164)

4- [2- [3- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] group]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Pyrazol-1-yl]Ethoxy radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (467mg, 0.6258 mmol) was dissolved in dichloromethane (10mL) and hydrochloric acid (4.5mL, 4M in dioxane, 18.00mmol) was added to the mixture and the mixture was stirred at room temperature for 30min the mixture was concentrated to dryness under reduced pressure and reacted with potassium carbonate (520mg, 3.763mmol), cesium fluoride (154mg, 1.014mmol),

Molecular sieves and dimethylsulfoxide (10mL) were combined in a vial, purged with nitrogen, capped, heated to 140 ℃, and stirred for 16h ₁₈Column (30% -99% acetonitrile-water +5mM hydrochloric acid) to give 20, 20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid]Ethoxy } -1H-pyrazol-1-yl) -17-oxa-10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2 (7), 3, 5, 11(22), 12-pentaen-8, 10, 10-trione (compound 164) (115mg, 30%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.74(s, 1H), 8.17(d, J ═ 2.8Hz, 1H), 7.96(s, 1H), 7.69(d, J ═ 8.2Hz, 1H), 6.89(d, J ═ 8.2Hz, 2H), 6.08(d, J ═ 2.8Hz, 1H), 4.42(t, J ═ 13.0Hz, 1H), 4.38-4.07(m, 5H), 3.88(t, J ═ 11.4Hz, 1H), 2.88(s, 1H), 2.18-2.03(m, 2H), 2.01(dd, J ═ 11.5, 6.0Hz, 1H), 1.78(t, J ═ 9.1Hz, 1H), 1.61(t, J ═ 11.5, 1H), 1.92 (s, 3.54H), 3.84 (s, 3.0H), 3.84H, 1H, and 1.8H. ESI-MS m/z calculated 609.1981,experimental value 610.36(M +1)⁺(ii) a Retention time: 2.03min (LC method B).

And 4, step 4: 20, 20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -17-oxa-10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7 ]Docosac-2 (7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 1) (compound 302) and 20, 20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -17-oxa-10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2 (7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 167)

To the racemic compound 20, 20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl]Ethoxy } -1H-pyrazol-1-yl) -17-oxa-10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Dodecan-2 (7), 3, 5, 11(22), 12-pentaen-8, 10, 10-trione (compound 164) (98mg, 0.1591mmol) was subjected to chiral preparative SFC for separation of enantiomers the following SFC scheme was employed: ChiralPak AS-3 (150X 2.1mm), 3 μm; 35 ℃, mobile phase: 30% acetonitrile: methanol (90: 10), 70% carbon dioxide the first enantiomer to be eluted was 20, 20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] isomer]Ethoxy } -1H-pyrazol-1-yl) -17-oxa-10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7 ]Docosal-2 (7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 1) (compound 302) (31mg, 63%); ESI-MS M/z calculated 609.1981, Experimental 610.32(M +1)⁺(ii) a Retention time: 2.01min (LC method B.) the second enantiomer to be eluted was 20, 20-dimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] isomer]Ethoxy } -1H-pyrazol-1-yl) -17-oxa-10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosate-2 (7), 3, 5, 11(22)12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 167) (31mg, 63%); ESI-MS M/z calculated 609.1981, Experimental 610.28(M +1)⁺(ii) a Retention time: 2.0min (LC method B).

Example 162: preparation of 4-chloro-20, 20-dimethyl-10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (enantiomer 1) and 4-chloro-20, 20-dimethyl-10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 2)

Step 1: 4-chloro-20, 20-dimethyl-10 lambda ⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (enantiomer 1) (compound E) and 4-chloro-20, 20-dimethyl-10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 2) (Compound F)

For racemic 4-chloro-20, 20-dimethyl-10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Dodecan-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (498mg) was subjected to chiral SFC chromatography. The following SFC protocol was employed: ChiralPak AS-H (250X 21.2mm), 5 μm; 35 ℃, mobile phase: 18% acetonitrile: methanol (90: 10), 82% carbon dioxide, flow rate 70mL/min the first enantiomer to be eluted was 4-chloro-20, 20-dimethyl-10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione(enantiomer 1) (162mg, 13%).¹H NMR (400MHz, chloroform-d) 8.73(s, 1H), 7.57-7.45(M, 2H), 7.06(d, J ═ 2.3Hz, 1H), 6.49(d, J ═ 7.8Hz, 1H), 4.28(dt, J ═ 13.4, 3.3Hz, 1H), 4.02-3.85 (M, 1H), 2.67(s, 1H), 2.13(dt, J ═ 11.4, 5.3Hz, 2H), 2.08-1.98(M, 1H), 1.92 (dt, J ═ 15.4, 10.2Hz, 2H), 1.77-1.70(M, 1H), 1.54(s, 3H), 1.49(s, 3H), 1.44(t, J ═ 12.3H, 1H), 0.83-0.84 (M, 1H), experimental calculated values (M, 3H), 1.84-M, 853H), 1.44 (M, 3H), 1.83, M, 35857H), experimental values (M, M + 853H) ⁺(ii) a Retention time: 1.66min (LC method B). The second enantiomer to be eluted was 4-chloro-20, 20-dimethyl-10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 2) (163mg, 13%).¹H NMR (400 MHz, chloroform-d) 8.82(s, 1H), 7.57-7.45(m, 2H), 7.06(d, J ═ 2.3Hz, 1H), 6.49(d, J ═ 7.8Hz, 1H), 4.27(dt, J ═ 13.3, 3.4Hz, 1H), 4.01-3.87(m, 1H), 2.67(s, 1H), 2.24-2.07 (m, 2H), 2.08-1.98(m, 1H), 2.00-1.84(m, 2H), 1.82-1.68(m, 1H), 1.54(s, 3H), 1.49(s, 3H), 1.44(t, J ═ 12.3Hz, 1H), 0.77 (18.8, 9.0, 1H). ESI-MS M/z calculated 423.1132, Experimental 424.04(M +1)⁺(ii) a Retention time: 1.67min (LC method B).

Example 163: preparation of 4- [3- (3, 3-dimethylbutyl) -2-oxoimidazolidin-1-yl radical]-20, 20-dimethyl-10. lambda.⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (Compound 168)

Step 1: 4- [3- (3, 3-dimethylbutyl) -2-oxoimidazolidin-1-yl radical ]-20, 20-dimethyl-10. lambda.⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (Compound 168)

4-chloro-20, 20-dimethyl-10. lambda. in a vial by purging with nitrogen for 2min⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosate-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (75mg, 0.1769mmol), 1- (3, 3-dimethylbutyl) imidazolidin-2-one (38mg, 0.2232 mmol), sodium tert-butoxide (27mg, 0.2809mmol) and chlorine (2-di-tert-butylphosphino-2 ', 4', 6 '-triisopropyl-1, 1' -biphenyl) [2- (2-aminoethyl) phenyl ]]A solution of palladium (II) (31mg, 0.04760mmol) in dioxane (2mL) was degassed then the mixture was stirred at room temperature for 1h, the reaction mixture was quenched with 0.5mL acetic acid and filtered through Whatman filter disc (puradisc 25TF) using a small amount of dimethyl sulfoxide and the filtrate was purified by reverse phase HPLC-MS method using a double gradient run of 50% -99% mobile phase B over 15.0min (mobile phase a ═ water (5mM hydrochloric acid), mobile phase B ═ acetonitrile, flow rate 50mL/min, injection volume of 950 μ L and column temperature of 25 ℃) to give 4- [3- (3, 3-dimethylbutyl) -2-oxoimidazolidin-1-yl as a white solid ]-20, 20-dimethyl-10. lambda.⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (compound 168) (24mg, 24%).¹H NMR (400MHz, chloroform-d) 8.38(s, 1H), 7.55(s, 2H), 7.46(d, J ═ 2.3Hz, 1H), 7.05(d, J ═ 2.3Hz, 1H), 4.35(d, J ═ 11.7Hz, 1H), 3.96(dt, J ═ 36.5, 11.0Hz, 3H), 3.46(d, J ═ 8.4Hz, 2H), 3.39-3.27(M, 2H), 2.71(s, 1H), 2.12(s, 2H), 2.02(s, 2H), 1.92(s, 1H), 1.72(d, J ═ 8.8Hz, 1H), 1.55(s, 3H), 1.49(s, 3H), 1.45(dd, J ═ 10.6, 6H), 7.83 (d, J ═ 8H, 1H), 7.84 (z + 3H), calculated values of M, 2H), 1.84 (d, 3H), 1.8H, 1H, 1.8 (dd, ESI, 7H), calculated values of M, 7H, 3H), and M⁺(ii) a Retention time: 1.84min (LC method B).

Example 164: preparation of 4- [3- (4, 4-dimethylpentyl) -2-oxoimidazolidin-1-yl radical]-20, 20-dimethyl-10. lambda.⁶Thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02,7]docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (Compound 169)

Step 1: 4, 4-dimethyl valeronitrile

1-bromo-3, 3-dimethyl-butane (25g, 151.45mmol) was slowly added to a suspension of sodium cyanide (8.17 g, 166.71mmol) in dimethyl sulfoxide (80mL) at 60 ℃ keeping the internal temperature between 55 ℃ and 65 ℃. The reaction mixture was heated at 70 ℃ for 90min, then cooled to room temperature, the reaction mixture was diluted with water (300mL) and extracted with diethyl ether (3 × 150mL), the organic layers were combined, washed with 5N hydrochloric acid (75mL) and water (75mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 4, 4-dimethylvaleronitrile (17.82g, 89%) as a clear oil. ¹H NMR (300MHz，CDCl₃)ppm 0.93(s，9H)，1.56-1.67(m，2H)，2.28(dd，J＝8.8，7.3Hz， 2H).

Step 2: 4, 4-Dimethylpentanal

Diisobutylaluminum hydride (226mL, 1M in dichloromethane, 226.00mmol) was added to a solution of 4, 4-dimethylvaleronitrile (16.75g, 150.65mmol) in dichloromethane (560mL) at 0 deg.C the reaction mixture was stirred at 0 deg.C for 90min, followed by quenching with 3M hydrochloric acid. The aqueous layer was separated and extracted with dichloromethane. The combined organic layers were washed with 10% hydrochloric acid, water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 4, 4-dimethylpentanal (16.23g, 94%) as a yellow oil.¹H NMR(300MHz，CDCl₃)ppm 0.90(s，9H)，1.46-1.61(m，2H)，2.40(td，J＝8.1，1.9Hz，2H)，9.78(t，J＝1.9Hz，1H)。

And step 3: n- [2- (4, 4-Dimethylpentylamino) ethyl ] carbamic acid tert-butyl ester

4, 4-Dimethylpentanal (15.2g, 133.12mmol) was added to a solution of tert-butyl N- (2-aminoethyl) carbamate (20.948g, 20.7mL, 130.75mmol) in methanol (300mL) and the reaction mixture was stirred at room temperature for 1h once the reaction mixture was cooled to 0 deg.C, sodium borohydride (5.2g, 137.45 mmol) was slowly added and the mixture was stirred at room temperature overnight. The residue was dissolved in ethyl acetate (300mL) and washed with saturated aqueous sodium bicarbonate (2X 300mL) and brine (300mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give N- [2- (4, 4-dimethylpentylamino) ethyl as a yellow oil ]Tert-butyl carbamate (21.83g, 65%). the crude material was used in the next step without any further purification ESI-MS calculated M/z 258.2307, experimental 259.3(M +1)⁺(ii) a Retention time: 1.39min (LC method I).

And 4, step 4: 1- (4, 4-dimethylpentyl) imidazolidin-2-one

Solid potassium tert-butoxide (28.6g, 254.87mmol) was added to N- [2- (4, 4-dimethylpentylamino) ethyl]A solution of tert-butyl carbamate (21.83g, 84.481mmol) in tetrahydrofuran (260mL) was added and the reaction mixture was heated at 60 ℃ for 3 h. Once cooled to room temperature, the reaction mixture was acidified to pH 1-2 with aqueous hydrochloric acid (1M) and concentrated under reduced pressure the aqueous residue was extracted with ethyl acetate (3 × 250mL) and the organic layers were combined, washed with brine (2 × 200mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. By silica gel chromatography using 0% to 10% methanol/ethanolThe residue was purified by gradient of ethyl acetate to give 1- (4, 4-dimethylpentyl) imidazolidin-2-one as an off-white solid (7.36g, 45%).¹H NMR (300MHz, dimethylsulfoxide-d)₆) ppm 0.84(s, 9H), 1.02-1.15(m, 2H), 1.28-1.43(m, 2H), 2.96(t, J ═ 7.2Hz, 2H), 3.14-3.22(m, 2H), 3.23-3.31(m, 2H), 6.20(br.s., 1H). ESI-MS M/z calculated 184.1576, Experimental 185.3(M +1) ⁺(ii) a Retention time: 2.34min (LC method H).

And 5: 4- [3- (4, 4-dimethylpentyl) -2-oxoimidazolidin-1-yl radical]-20, 20-dimethyl-10. lambda.⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (Compound 169)

4-chloro-20, 20-dimethyl-10. lambda. in a vial by purging with nitrogen for 2min⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosate-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (30mg, 0.07077mmol), 1- (4, 4-dimethylpentyl) imidazolidin-2-one (16mg, 0.08683mmol), sodium tert-butoxide (12mg, 0.1249mmol) and chlorine (2-di-tert-butylphosphino-2 ', 4', 6 '-triisopropyl-1, 1' -biphenyl) [2- (2-aminoethyl) phenyl ]]A solution of palladium (II) (14mg, 0.02150mmol) in dioxane (2mL) was degassed the mixture was stirred at room temperature for about 1h, quenched with 0.5mL acetic acid and filtered using a small amount of dimethyl sulfoxide through Whatman filter disc (puradisc 25TF) and the filtrate was purified by reverse phase HPLC-MS method using a double gradient run of 50% -99% mobile phase B over 15.0min (mobile phase a ═ water (5mM hydrochloric acid), mobile phase B ═ acetonitrile, flow rate ═ 50mL/min, injection volume ═ 950 μ L and column temperature ═ 25 ℃) to give 4- [3- (4, 4-dimethylpentyl) -2-oxoimidazolidin-L-yl as an off-white solid ]-20, 20-dimethyl-10. lambda.⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (Compound 169) (6.8 mg)，16％).¹H NMR (400MHz, chloroform-d) 8.54(s, 1H), 7.54(s, 2H), 7.46(d, J ═ 2.2Hz, 1H), 7.05(d, J ═ 2.1Hz, 1H), 4.35(d, J ═ 13.2Hz, lH), 4.09-3.85(M, 3H), 3.46(d, J ═ 8.7Hz, 2H), 3.27(t, J ═ 7.3 Hz, 2H), 2.71(s, 1H), 2.11(s, 3H), 1.99-1.85(M, 1H), 1.71(dd, J ═ 11.7, 5.3Hz, 1H), 1.60(s, 3H), 1.55(s, 3H), 1.49(s, 3H), 1.48-1.35(M, 1H), 17(M, 17H), 17H), 2H, 17(M, 2H), 2H, 18H), and calculated values (M, 17H)⁺(ii) a Retention time: 2.02min (LC method B).

Example 165: preparation of (14S) -8- [3- (3, 3-dimethylbutoxy) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 170) and (14S) -8- [3- (3, 3-dimethylbutoxy) -2-oxopyrrolidin-1-yl ]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 171)

Step 1: 3- (3, 3-dimethylbutoxy) pyrrolidin-2-one

To a stirred solution of 3, 3-dimethylbut-1-ol (540mg, 5.285mmol) in anhydrous tetrahydrofuran (20mL) at ambient temperature under nitrogen was added [ bis (trimethylsilyl) amino group]Potassium (10.6mL, 0.5M in toluene, 5.300 mmol). The opalescent reaction was stirred for 30min, followed by dropwise addition of a solution of 3-bromopyrrolidin-2-one (830mg, 4.808mmol) in anhydrous tetrahydrofuran (3mL) at 0 deg.C (ice-water bath) the reaction was gradually warmed to ambient temperature overnight (18 h)). The reaction was acidified with 1M aqueous hydrochloric acid (1.5mL) and the volatiles were removed under reduced pressure the residue was dissolved in ethyl acetate (30mL) and washed with brine (15 mL). The organic portion was dried (anhydrous sodium sulfate), filtered and concentrated under reduced pressure to give a light brown crude material. The crude material was purified by silica gel chromatography (gradient of 0% to 10% methanol in dichloromethane) to give 3- (3, 3-dimethylbutoxy) pyrrolidin-2-one (143mg, 16%) as a white solid. ESI-MS M/z calculated 185.14159, Experimental 186.2(M +1) ⁺(ii) a Retention time: 0.95min (LC method B).

Step 2: (14S) -8- [3- (3, 3-dimethylbutoxy) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione

Sequentially adding (14S) -8-chloro-12, 12-dimethyl-2 lambda to the vial⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (100mg, 0.2222mmol), 3- (3, 3-dimethylbutoxy) pyrrolidin-2-one (50mg, 0.2699mmol), cesium carbonate (290mg, 0.8901mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (20mg, 0.03457mmol) (Xantphos) and anhydrous dioxane (2 mL.) nitrogen was purged through the heterogeneous mixture for 3min followed by Pd addition under nitrogen₂(dba)₃(20mg, 0.02184mmol) and nitrogen purged into the vial for an additional 2min, followed by capping under nitrogen. The mixture was stirred at 115 ℃ for 15h the mixture was cooled to ambient temperature and neutralized with glacial acetic acid (130 μ L, 2.286 mmol). The volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (3.0mL) and filtered through Whatman 0.45 μm PTFE syringe filter the sample was purified using preparative reverse phase HPLC-MS (gradient of 30% -99% acetonitrile/water over 15min (hydrochloric acid as modifier)), the desired product fractions were combined and concentrated under reduced pressure, and the residue was dissolved in dimethyl sulfoxide (3.0mL) The residue was dissolved in ethyl acetate (25 mL) and washed with brine (10 mL.) the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a mixture of diastereomers as an off-white solid, i.e. (14S) -8- [3- (3, 3-dimethylbutoxy) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (27mg, 20%).¹H NMR (400MHz, methanol-d)₄)7.78(dd, J ═ 8.4, 2.1Hz, 1H), 7.60(dd, J ═ 8.4, 4.3 Hz, 1H), 7.53(dd, J ═ 8.5, 7.2Hz, 1H), 7.16(dt, J ═ 7.2, 1.0Hz, 1H), 6.65(d, J ═ 8.5 Hz, 1H), 4.25(dt, J ═ 12.8, 8.0Hz, 1H), 4.20-3.99(m, 2H), 3.97-3.76(m, 2H), 3.74-3.65 (m, 1H), 3.03(d, J ═ 13.8Hz, 1H), 2.86(t, J ═ 9.9Hz, 1H), 2.56-2.44(m, 1H), 17.17 (d, J ═ 13.8Hz, 1H), 2.86(t, J ═ 9.9, 1H), 2.56-2.44(m, 1H), 17.84 (t, 1H), 7.6.6H, 1H), 7.6H, 1H, 6H, 1H, 6H, 1H. ESI-MS M/z calculated 598.29376, Experimental 651.4(M +1)⁺(ii) a Retention time: 2.04min (LC method B).

And step 3: (14S) -8- [3- (3, 3-dimethylbutoxy) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 170) and (14S) -8- [3- (3, 3-dimethylbutoxy) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 171)

To the racemic diastereomer (14S) -8- [3- (3, 3-dimethylbutoxy) -2-oxopyrrolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10%]Chiral SFC chromatography of tetracosene-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione using the following SFC protocol: ChiralCel OJ-H (250X 10mm), 5 μm; mobile phase: 20% acetonitrile: methanol (90: 10; no modifier), 80% carbon dioxide, flow rate 10mL/min, to provide (14S) -8- [3- (3, 3-dimethylbutoxy) -2-oxopyrrolidin-1-yl as the first diastereomer to be eluted ]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 170) (11mg, 8%);¹h NMR (400MHz, dimethylsulfoxide-d)₆)12.43(s, 1H), 7.70(d, J ═ 8.3Hz, 1H), 7.57(t, J ═ 7.8Hz, 1H), 7.51(d, J ═ 8.3Hz, 1H), 7.04(d, J ═ 7.2Hz, 1H), 6.96(s, 1H), 6.70(d, J ═ 8.5Hz, 1H), 4.23(t, J ═ 8.0Hz, 1H), 4.07-3.98(m, 1H), 3.88(dt, J ═ 8.8, 7.2Hz, 2H), 3.70(dt, J ═ 10.5, 7.6Hz, 1H), 3.60(dt, J ═ 9.2, 7.2Hz, 1H), 3.20-3.94 (m, 2H), 2.94(d, 1H), 1.68, 1H), 1H, 13.8, 1H, 18, 1H, 1, 1.64-1.57(M, 2H), 1.57(s, 3H), 1.52-1.48(M, 2H), 1.46(s, 3H), 1.34-1.26(M, 1H), 1.24(s, 1H), 0.91 (d, J ═ 0.9Hz, 9H), calculated ESI-MS M/z 598.29376, experimental 599.4(M +1)⁺(ii) a Retention time: 2.21min (LC method B) and (14S) -8- [3- (3, 3-dimethylbutoxy) -2-oxopyrrolidin-1-yl) as second diastereomer to be eluted ]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 171) (10mg, 7%);¹h NMR (400MHz, dimethylsulfoxide-d)₆)12.41(s，1H)， 7.70(d，J＝8.4Hz，1H)，7.57(t，J＝7.9Hz，1H)，7.53(d，J＝8.4Hz，1H)，7.04(d，J＝7.2Hz，1H)，6.96(s，1H)，6.70(d，J＝8.5Hz，1H)，4.28(t，J＝8.3Hz，1H)，3.97- 3.92(m, 1H), 3.92-3.89(m, 1H), 3.89-3.84(m, 1H), 3.77(dt, J ═ 10.2, 7.5Hz, 1H), 3.59(ddd, J ═ 9.3, 7.7, 6.7Hz, 1H), 3.16-3.03(m, 1H), 2.94(d, J ═ 13.3Hz, 1H), 2.74-2.64(m, 1H), 2.48-2.39(m, 1H), 2.20-2.02(m, 1H), 1.93-1.85(m, 1H), 1.84-1.79(m, 1H), 1.79-1.69(m, 1H), 1.63-1.57(m, 2H), 1.57(s, 3H), 1.52-1.47 (m, 1H), 1.46H, 1H), 1H (m, 1H), 1H, 1.47 (m, 1H), 1H. ESI-MS M/z calculated 598.29376, Experimental 599.4(M +1)⁺(ii) a Retention time: 2.18min (LC method B).

Example 166: preparation of (14S) -12, 12-dimethyl-8- (2-oxo-3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } pyrrolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 172) and (14S) -12, 12-dimethyl-8- (2-oxo-3- {2- [1- (trifluoromethyl) cyclopropyl ]Ethoxy } pyrrolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 173)

Step 1: (14S) -12, 12-dimethyl-8- (2-oxo-3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } pyrrolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 172) and (14S) -12, 12-dimethyl-8- (2-oxo-3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } pyrrolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 173)

For the diastereomer mixture (14S) -12, 12-dimethyl-8- (2-oxo-3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } pyrrolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (dihydrochloride) (31mg) was purified by chiral SFC. The SFC purification method employed used ChiralCel OJ-H (250X 10mm), 5 μm column; mobile phase: 20% acetonitrile to methanol (90: 10; no modifier), 80% carbon dioxide; flow rate: 10 mL/min; sample concentration: about 24mg/mL in acetonitrile: methanol: dimethyl sulfoxide (85: 9: 6); injection volume: 70 mu L of the solution; pressure: 100 bar. The first diastereomer to elute was (14S) -12, 12-dimethyl-8- (2-oxo-3- {2- [1- (trifluoromethyl) cyclopropyl ]Ethoxy } pyrrolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 1) (compound 172) (7mg, 5%). ESI-MS M/z calculated 650.2498, Experimental 651.4(M +1)⁺(ii) a Retention time: 2.09min (LC method B). The second diastereomer to elute was (14S) -12, 12-dimethyl-8- (2-oxo-3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } pyrrolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (diastereomer 2) (compound 173) (7mg, 5%). ESI-MS M/z calculated 650.2498, Experimental 651.4(M +1)⁺(ii) a Retention time: 2.09min (LC method B).

Example 167: preparation of 20, 20-dimethyl-4- (2-oxo-3- {3- [1- (trifluoromethyl) cyclopropyl]Propyl } pyrrolidin-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (diastereomer 1) (compound 181) and 20, 20-dimethyl-4- (2-oxo-3- {3- [1- (trifluoromethyl) cyclopropyl ]Propyl } pyrrolidin-1-yl) -10 lambda⁶Thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (diastereomer 2) (compound 182)

Step 1: 20, 20-dimethyl-4- (2-oxo-3- {3- [1- (trifluoromethyl) cyclopropyl]Propyl } pyrrolidin-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (diastereomer 1) (compound 181) and 20, 20-dimethyl-4- (2-oxo-3- {3- [1- (trifluoromethyl) cyclopropyl]Propyl } pyrrolidin-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (diastereomer 2) (compound 182)

Sequentially adding 4-chloro-20, 20-dimethyl-10 lambda to the vial⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docodeca-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 2) (40 mg, 0.09436mmol), 3- [3- [1- (trifluoromethyl) cyclopropyl]Propyl radical]Pyrrolidin-2-one (27mg, 0.1148 mmol), cesium carbonate (110mg, 0.3376mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (9mg, 0.01555mmol) (Xantphos), and anhydrous dioxane (2mL) ₂(dba)₃(9mg, 0.009960mmol) and nitrogen was bubbled through the reaction for an additional 2min, and then the mixture was capped under nitrogen the mixture was stirred at 115 ℃ for 15h the mixture was cooled to ambient temperature and neutralized with glacial acetic acid (50 μ L, 0.8792 mmol). Volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.5mL) and passed through Whatman 0.45 μm PTFE syringe filter. The sample was purified using preparative reverse phase HPLC-MS (30% to 99% acetonitrile/water over 15min (hydrochloric acid as modifier)), the desired product fractions were combined and concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (25mL) and washed successively with saturated aqueous sodium bicarbonate (2 × 10mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a mixture of diastereomers as an off-white solid, i.e., 20-dimethyl-4- (2-oxo-3- {3- [1- (trifluoromethyl) cyclopropyl]Propyl } pyrrolidin-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (41mg, 70%), using ChiralCel OJ-3H (250X 10mm), 5 μm column; mobile phase: 20% acetonitrile to methanol (90: 10; no modifier), 80% carbon dioxide; flow rate: 10 mL/min; concentration: about 24mg/mL in acetonitrile: methanol: dimethyl sulfoxide (81: 9: 10); injection volume: 70 mu L of the solution; pressure: 100 bar; wavelength: the mixture of diastereomers was subjected to chiral SFC purification at 242 nm. The first diastereomer to elute was 20, 20-dimethyl-4- (2-oxo-3- {3- [1- (trifluoromethyl) cyclopropyl ]Propyl } pyrrolidin-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (diastereomer 1) (compound 181) (11mg, 18%). ESI-MS M/z calculated 622.2549, Experimental 623.4(M +1)⁺(ii) a Retention time: 2.18min (LC method B.) the second diastereomer to be eluted was 20, 20-dimethyl-4- (2-oxo-3- {3- [1- (trifluoromethyl) cyclopropyl ]]Propyl } pyrrolidin-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (diastereomer 2) (compound 182) (10mg, 17%). ESI-MS M/z calculated 622.2549, Experimental value 623.4(M +1)⁺(ii) a Retention time: 2.19min (LC method B).

Example 168: preparation of 20, 20-dimethyl-4- (2-oxo-3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } pyrrolidin-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22Pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (compound 183), 20-dimethyl-4- (2-oxo-3- {2- [1- (trifluoromethyl) cyclopropyl ]Ethoxy } pyrrolidin-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (diastereomer 1) (compound 191) and 20, 20-dimethyl-4- (2-oxo-3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } pyrrolidin-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (diastereomer 2) (compound 192)

Step 1: 20, 20-dimethyl-4- (2-oxo-3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } pyrrolidin-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (Compound 183)

Sequentially adding 4-chloro-20, 20-dimethyl-10 lambda to the vial⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docodeca-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 2) (40 mg, 0.09436mmol), 3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrrolidin-2-one (23mg, 0.09696mmol), cesium carbonate (102mg, 0.3131mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (8mg, 0.01383mmol) (Xantphos), and anhydrous dioxane (1.5 mL). Bubbling nitrogen through the heterogeneous mixture for 2min, followed by addition of Pd under nitrogen ₂(dba)₃(8mg, 0.008853mmol) and nitrogen was bubbled through the reaction for an additional 2min, followed by capping under nitrogen 1The mixture was stirred at 15 ℃ for 15h the mixture was cooled to ambient temperature and neutralized with glacial acetic acid (50 μ L, 0.8792mmol), the volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.5mL), and filtered through Whatman 0.45 μm PTFE syringe filter the sample was purified using preparative reverse phase HPLC-MS (30% -99% acetonitrile/water over 15min, hydrochloric acid as modifier), the desired product fractions were combined and concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (25mL) and washed successively with a saturated aqueous solution of sodium bicarbonate (2 × 10mL) and brine (10 mL.) the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 20, 20-dimethyl-4- (2-oxo-3- {2- [1- (trifluoromethyl) cyclopropyl as an off-white solid.]Ethoxy } pyrrolidin-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (compound 183) (41mg, 74%).¹H NMR (400MHz, methanol-d)₄)7.79(d, J ═ 2.3Hz, 1H), 7.64(dd, J ═ 8.4, 2.1Hz, 1H), 7.61-7.54(m, 1H), 6.91(dd, J ═ 2.4, 1.1Hz, 1H), 4.31-4.21(m, 2H), 4.16(ddd, J ═ 11.8, 8.8, 3.2Hz, 1H), 4.12-4.00(m, 1H), 3.96(q, J ═ 7.5Hz, 1H), 3.90-3.72(m, 2H), 2.83-2.73(m, 1H), 2.55-2.43(m, 1H), 2.23-2.08(m, 2H), 2.02-1.87(m, 6H), 1.77 (ddl, 1H), 1.76 (m, 1H), 0.76-0.76H), 1H (m, 1H), 1H, 0.76H, 0, 0.76, 1H, 0, 1H, 0, 1H. ESI-MS M/z calculated 624.2342, Experimental 625.4 (M +1) ⁺(ii) a Retention time: 2.05min (LC method B).

Step 2: 20, 20-dimethyl-4- (2-oxo-3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } pyrrolidin-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (diastereomer 1) (compound 191) and 20, 20-dimethyl-4- (2-oxo-3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } pyrrolidin-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosal-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (diastereoisomers)Body 2) (Compound 192)

ChiralPak IG (250X 10mm), 5 μm column; mobile phase: 42% acetonitrile to methanol (90: 10; no modifier), 58% carbon dioxide; flow rate: 70 mL/min; concentration: about 24mg/mL in acetonitrile: methanol (90: 10, no modifier); injection volume: 70 mu L of the solution; pressure: 100 Bar pairs of 20, 20-dimethyl-4- (2-oxo-3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } pyrrolidin-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]The docosal-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (compound 183) is subjected to chiral SFC. The first diastereomer to elute was 20, 20-dimethyl-4- (2-oxo-3- {2- [1- (trifluoromethyl) cyclopropyl ]Ethoxy } pyrrolidin-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (diastereomer 1) (compound 191) (13.6mg, 24%). ESI-MS M/z calculated 624.2342, Experimental 625.4(M +1)⁺(ii) a Retention time: 1.87min (LC method B). The second diastereomer to elute was 20, 20-dimethyl-4- (2-oxo-3- {2- [1- (trifluoromethyl) cyclopropyl-]Ethoxy } pyrrolidin-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (diastereomer 2) (compound 192) (13.5mg, 24%). ESI-MS M/z calcd 624.2342, Experimental 625.4(M +1)⁺(ii) a Retention time: 1.88min (LC method B).

Example 169: preparation of 4- [3- (3, 3-dimethylbutyl) -2-oxopyrrolidin-1-yl]-20, 20-dimethyl-10. lambda.⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (compound 184)

Step 1: 4- [3- (3, 3-dimethylbutyl) -2-oxopyrrolidin-1-yl]-20, 20-dimethyl-10. lambda. ⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (compound 184)

Sequentially adding 4-chloro-20, 20-dimethyl-10 lambda to the vial⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (enantiomer 1) (11 mg, 0.02595mmol), 3- (3, 3-dimethylbutyl) pyrrolidin-2-one (8mg, 0.04726mmol), cesium carbonate (32mg, 0.09821mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (3mg, 0.005185 mmol) (Xantphos) and anhydrous dioxane (0.8 mL). Nitrogen was bubbled through the heterogeneous mixture for 2 min. Subsequently, Pd was added under nitrogen₂(dba)₃(3mg, 0.003320mmol) and nitrogen was bubbled through the mixture for an additional 2min and the mixture was capped under nitrogen the mixture was stirred at 115 ℃ for 13 h. The mixture was cooled to ambient temperature and neutralized with glacial acetic acid (20 μ L, 0.3517 mmol.) the volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.0mL) and filtered through Whatman 0.45 μm PTFE syringe filter sheet the sample was purified using preparative reverse phase HPLC-MS (30% -99% acetonitrile/water over 15min (hydrochloric acid as modifier).) the desired product fractions were combined and concentrated under reduced pressure to give 4- [3- (3, 3-dimethylbutyl) -2-oxopyrrolidin-1-yl as a pale yellow solid ]-20, 20-dimethyl-10. lambda.⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (compound 184) (7.5mg, 51%).¹H NMR (400MHz, methanol-d)₄)7.78(d，J＝2.5Hz，1H)，7.67- 7.60(m，1H)，7.56(dd，J＝8.5，7.0Hz，1H)，6.91(d，J＝2.4Hz，1H)，4.33-4.22(m1H), 4.20-4.11(M, 1H), 4.10-3.97(M, 1H), 3.96-3.78(M, 1H), 2.83-2.73(M, 1H), 2.62(ddd, J ═ 13.7, 9.4, 5.0Hz, 1H), 2.31(q, J ═ 9.0Hz, 1H), 2.21-2.08(M, 2H), 2.04-1.84(M, 4H), 1.81-1.69(M, 2H), 1.57(s, 3H), 1.51(s, 3H), 1.39(t, J ═ 12.4 Hz, 2H), 1.33-1.27(M, 2H), 0.92(s, 9H), 0.79-0.66(M, 1H), ESI-M/556.2832, experimental value (M, 2H), 557 + 5M + 557)⁺(ii) a Retention time: 2.23min (LC method B).

Example 170: preparation of (18R) -4- [3- (2- { dispiro [2.0.2.1]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-20, 20-dimethyl-10. lambda.⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (compound 186)

Step 1: 4- [3- [3- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1] hept-7-ylethoxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] pyrazol-1-yl ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- (2-dispiro [2.0.2.1 ]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (400mg, 1.112mmol) and carbonyldiimidazole (273.5mg, 1.687mmol) were combined in tetrahydrofuran (2mL) and stirred at room temperature for 90 min. Subsequently, 2-dimethyl-4- [3- (3-sulfamoylpyrazol-1-yl) propyl ] is added]Pyrrolidine-1-carboxylic acid tert-butyl ester (429.5mg, 1.111mmol) followed by addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (430.8mg, 2.830mmol) and the reaction stirred at room temperature for 1h, then heated to 50 ℃ and stirred overnight. The reaction was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate followed by brine. The organics were separated, dried over sodium sulfate, filtered and evaporated, and then chromatographed on silica gel using 100% hexaneGradient purification to 100% ethyl acetate afforded 4- [3- [3- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1 ]) as an off-white solid]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Pyrazol-1-yl]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (350mg, 43%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)8.34(s, 1H), 8.08(d, J ═ 8.2Hz, 1H), 7.77(s, 1H), 7.62 (d, J ═ 8.3Hz, 1H), 6.71-6.49(m, 1H), 6.10(d, J ═ 2.8Hz, 1H), 4.23(s, 2H), 4.13(s, 2H), 3.52(s, 1H), 2.73(d, J ═ 6.0Hz, 1H), 2.08(d, J ═ 6.7Hz, 1H), 1.81(q, J ═ 6.6 Hz, 5H), 1.47(t, J ═ 6.5Hz, 1H), 1.40-1.21(m, 18H), 0.83(d, J ═ 2.0, 4H), 0.66 (m, 60.52H), 0.46-2H, 52H, and 2H). ESI-MS M/z calculated 727.2919, Experimental 728.1 (M +1) ⁺(ii) a Retention time: 0.92min (LC method A).

Step 2: 2-chloro-N- [1- [3- (5, 5-dimethylpyrrolidin-3-yl) propyl ] pyrazol-3-yl ] sulfonyl-6- [3- (2-dispiro [2.0.2.1] hept-7-ylethoxy) pyrazol-1-yl ] pyridine-3-carboxamide

Reacting 4- [3- [3- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Pyrazol-1-yl]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (350mg, 0.4806 mmol) was dissolved in dichloromethane (1.527mL) and trifluoroacetic acid (2.192g, 1.481mL, 19.22mmol) was added to the mixture and the resulting mixture was stirred at room temperature for 60min. (Note: the product has poor solubility in ethyl acetate under these conditions, and the addition of some methanol can help, requiring evaporation of the organic layer without the use of a solid desiccant.) concentration of the organic layer by rotary evaporation, followed by vacuum drying, gives 2-chloro-N- [1- [3- (5, 5-dimethylpyrrolidin-3-yl) propyl ] as an off-white solid]Pyrazol-3-yl]Sulfonyl-6- [3- (2-dispiro [2.0.2.1]]Hept-7-ylethoxy) pyrazol-1-yl ]Pyridine compound-3-carboxamide (301.9mg, 100%) which was used directly in the next step.¹H NMR (400MHz, chloroform-d) 8.28(d, J ═ 2.8Hz, 1H), 8.21(d, J ═ 8.3Hz, 1H), 7.61(d, J ═ 8.3Hz, 1H), 7.44(s, 1H), 6.67(s, 1H), 5.88 (d, J ═ 2.8Hz, 1H), 4.22(t, J ═ 6.8Hz, 2H), 4.17(s, 2H), 3.55(s, 1H), 3.03(s, 1H), 2.23(s, 1H), 1.88(d, J ═ 6.7Hz, 2H), 1.83(s, 3H), 1.48(s, 1H), 1.46-1.35(m, 5H), 1.35-1.24(m, 4H), 0.84(t, 1.84, 1H), 1.63 (d, 1H), 1.51H, 1H), 1H (d, 1H).

And step 3: 4- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-20, 20-dimethyl-10. lambda.⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione

Molecular sieves and dimethylsulfoxide (9.3mL) were combined in a vial, purged with nitrogen, capped, heated to 155 ℃ and stirred for 20 h. The mixture was then cooled to room temperature and filtered, then diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate, followed by brine. The organics were separated, dried over sodium sulfate, filtered and evaporated, and then purified by silica gel chromatography using a gradient of 100% hexane to 100% ethyl acetate (product eluted after reaching 100% ethyl acetate) to give 4- [3- (2- { dispiro [2.0.2.1 ] as a white solid ]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-20, 20-dimethyl-10. lambda.⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosate-2, 4, 6, 11(22),12-Pentagen-8, 10, 10-trione (117mg, 40%).¹H NMR (400MHz, chloroform-d) 8.37(s, 1H), 8.16(d, J ═ 2.8Hz, 1H), 7.68(d, J ═ 8.3Hz, 1H), 7.48(d, J ═ 2.3Hz, 1H), 7.26(s, 1H), 7.07(d, J ═ 2.3Hz, 1H), 7.02(d, J ═ 8.3Hz, 1H), 5.86(d, J ═ 2.8Hz, 1H), 4.36(d, J ═ 13.5Hz, 1H), 4.24(s, 2H), 3.95(d, J ═ 12.4Hz, 1H), 2.74(t, J ═ 8.1Hz, 1H), 2.15(d, J ═ 4.2, 2H), 2.08 (d, J ═ 12.4Hz, 1H), 1H, 2.74(t, J ═ 8.1H, 1H), 2.15(d, J ═ 4.2H, 2H), 3.93 (d, 3.5H, 1H, j ═ 1.2Hz, 2H). ESI-MS M/z calculated 591.26276, Experimental 592.4(M +1)⁺(ii) a Retention time: 2.37min (LC method B).

And 4, step 4: (18R) -4- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-20, 20-dimethyl-10. lambda.⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (compound 186)

4- [3- (2- { dispiro [2.0.2.1 ] was chromatographed by SFC using ChiralPak AS-H (250X 10mm, 5 μm particle size) and a 34% acetonitrile/methanol (90: 10)/66% carbon dioxide mobile phase (10mL/min over 8.0min) (infusion volume 70 μ L, 24mg/mL solution in acetonitrile/methanol (90: 10)) over 4- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-20, 20-dimethyl-10. lambda.⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]The docosane-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (103mg, 0.1741 mmol) was subjected to chiral separation to give (18R) -4- [3- (2- { dispiro [2.0.2.1 ] as the first enantiomer to be eluted]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-20, 20-dimethyl-10. lambda.⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (compound 186) (40.8mg, 79%). ESI-MS calculated m/z 591.26276, experimentValue 593.1(M +1)⁺(ii) a Retention time: 2.3min (LC method B).

Example 171: preparation of (14R) -12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 190)

Step 1: 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-3-yl) propylamino ] -2-pyridinyl ] sulfonyl ] -6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carboxamide

The mixture was charged with carbonyldiimidazole (216mg, 1.332mmol) and 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]A50 mL flask of pyridine-3-carboxylic acid (520mg, 1.334mmol) was evacuated, followed by backfilling with nitrogen, tetrahydrofuran (8mL) was added and the mixture was stirred at 50 ℃ for 1h, followed by addition of 2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (500mg, 1.212 mmol) and 1, 8-diazabicyclo [5.4.0]A solution of undec-7-ene (555mg, 3.646mmol) in tetrahydrofuran (3mL) and the mixture stirred at 50 ℃ overnight. The reaction was diluted with ethyl acetate and washed with water the organic phase was dried over sodium sulfate, evaporated in vacuo and purified by silica gel chromatography (0% to 50% ethyl acetate/hexanes) to give some pure fractions₁₈): combine pure fractions from silica gel column and preparative HPLC column to give the acylsulfonamide intermediate, which is dissolved in dioxane (5mL) and then treated with a solution of hydrochloric acid in dioxane (2 mL, 6M, 12.00mmol) and then stirred at room temperature for 2 h. The mixture was evaporated in vacuo and carbonated The residue was quenched with aqueous sodium bicarbonate. The white precipitate of product was filtered off and washed with ethyl acetate. The aqueous phase was additionally extracted with ethyl acetate. The organic extracts were dried over sodium sulfate, filtered and evaporated to give 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-3-yl) propylamino ] amino after drying in vacuo]-2-pyridyl]Sulfonyl radical]-6- [3- [3- [1- (trifluoromethyl) cyclopropyl]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxamide (343mg, 41%). ESI-MS M/z calculated 683.2268, Experimental 684.32(M +1)⁺(ii) a Retention time: 0.65min (LC method A).

Step 2: (14R) -12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Propoxy } -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (compound 190)

In a 5mL vial, cesium fluoride (160mg, 1.053mmol), potassium carbonate (360mg, 2.605 mmol) and

molecular sieves (600mg) and the vials evacuated and then backfilled with nitrogen next, 2-chloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-3-yl) propylamino ] was added]-2-pyridyl]Sulfonyl radical]-6- [3- [3- [1- (trifluoromethyl) cyclopropyl]Propoxy group ]Pyrazol-1-yl]A solution of pyridine-3-carboxamide (350mg, 0.5116mmol) in dimethyl sulfoxide (5mL) and the mixture was stirred at 150 ℃ overnight, the mixture was filtered and purified by preparative reverse phase HPLC (C)₁₈): chiral separation of the racemate using ChiralPak AS-H (250 × 10mm, 5 μm particle size) and a 28% acetonitrile/methanol (90: 10)/72% carbon dioxide mobile phase (injected volume 500 μ L, 32mg/mL solution in acetonitrile/methanol (90: 10)) by SFC chromatography to give (14R) -12, 12-dimethyl-8- (3- {3- [1- (trifluoromethyl) cyclopropyl ] isomer AS the first enantiomer to be eluted]Propoxy group} -1H-pyrazol-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (Compound 190) (82.3mg, 49%). ESI-MS M/z calculated 647.2502, Experimental 648.1(M +1)⁺(ii) a Retention time: 2.21min (LC method B).

Example 172: preparation of (14S) -8- [3- (4, 4-dimethylpentyl) -2-oxoimidazolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 193)

Step 1: (14S) -8- [3- (4, 4-dimethylpentyl) -2-oxoimidazolidin-1-yl radical]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 193)

Sequentially adding (14S) -8-chloro-12, 12-dimethyl-2 lambda to the vial⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (60mg, 0.1333mmol), 1- (4, 4-dimethylpentyl) imidazolidin-2-one (50mg, 0.2713mmol), cesium carbonate (155 mg, 0.4757mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (12mg, 0.02074mmol) (Xantphos), and anhydrous dioxane (2.0mL) nitrogen was bubbled through the heterogeneous mixture for 2min, then Pd was added under nitrogen₂(dba)₃(12mg, 0.01328mmol) and nitrogen was bubbled into the mixture for an additional 2min, and then the vial was capped under nitrogen the mixture was stirred at 115 ℃ for 13h Acetic acid (70 μ L, 1.231mmol) neutralized the volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.5mL) and filtered through a Whatman 0.45 μm PTFE syringe filter using preparative reverse phase HPLC-MS [ 30% -99% acetonitrile/water (hydrochloric acid as modifier)]And (5) purifying the sample. The desired product fractions were combined and concentrated under reduced pressure and further dried under high vacuum to give (14S) -8- [3- (4, 4-dimethylpentyl) -2-oxoimidazolidin-1-yl as a pale yellow solid]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 193) (29mg, 36%).¹H NMR (400MHz, methanol-d)₄)7.70(d, J ═ 8.6Hz, 1H), 7.52(dd, J ═ 8.5, 7.2Hz, 1H), 7.44(d, J ═ 8.6Hz, 1H), 7.15(d, J ═ 7.2Hz, 1H), 6.65(d, J ═ 8.5Hz, 1H), 4.14-3.94(m, 3H), 3.52(ddd, J ═ 9.8, 7.0, 3.2 Hz, 2H), 3.24(q, J ═ 7.2Hz, 3H), 3.09-2.97(m, 1H), 2.86(t, J ═ 10.4Hz, 1H), 2.23-2.08 (m, 1H), 1.83(dd, J ═ 11.3, 5.1, 65, 1H, 63.65 (t, 1.4 Hz, 1H), 1H, 11.23-2.08 (m, 1H), 1.83 (ddh, 11.3, 5.3.2H), 1H, 19, 1H), 1H, and 1H. ESI-MS M/z calculated 597.30975, Experimental 598.5(M +1) ⁺(ii) a Retention time: 2.08min (LC method B).

Example 173: preparation of 12, 20, 20-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2 (7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (compound 199)

Step 1: 3-iodo-1- [ (4-methoxyphenyl) methyl ] -4-methyl-pyrazole and 5-iodo-1- [ (4-methoxyphenyl) methyl ] -4-methyl-pyrazole (mixture of regioisomers)

N-iodosuccinimide (27.4g, 121.79mmol) was added to a solution of 4-methyl-1H-pyrazole (10 g, 121.80mmol) in dimethylformamide (100mL) at room temperature the mixture was stirred overnight, then poured into water (700mL) and extracted with ethyl acetate (4X 150 mL). The organic phases were combined and washed with water (3 × 150mL) and brine (150mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude iodinated intermediate to a solution of crude iodinated material (2g, 9.6154mmol) and potassium carbonate (2g, 14.471mmol) in acetonitrile (15mL) was added 1- (chloromethyl) -4-methoxy-benzene (1.5015g, 1.3mL, 9.5876 mmol). The mixture was stirred overnight at 80 ℃ before concentration under reduced pressure, the residue was suspended in dichloromethane (80mL), after stirring for 10min, the mixture was mixed with silica gel, after which it was concentrated, the residue was dried, loaded on a silica gel column and eluted with 0% -30% ethyl acetate/heptane to obtain 3-iodo-1- [ (4-methoxyphenyl) methyl ] methyl as a pale yellow solid ]-4-methyl-pyrazole and 5-iodo-1- [ (4-methoxyphenyl) methyl]-4-methyl-pyrazole (mixture of regioisomers) (1.36g, 43%). ESI-MS M/z calculated 328.0073, Experimental 329.0(M +1)⁺(ii) a Retention time: 2.02min (LC method I).

Step 2: 2-ethylhexyl 3- [1- [ (4-methoxyphenyl) methyl ] -4-methyl-pyrazol-3-yl ] sulfanylpropionate and 2-ethylhexyl 3- [2- [ (4-methoxyphenyl) methyl ] -4-methyl-pyrazol-3-yl ] sulfanylpropionate (mixture of regioisomers)

In a sealed tube, 3-iodo-1- [ (4-methoxyphenyl) methyl group was caused to be present by bubbling nitrogen gas for 5min]-4-methyl-pyrazole and 5-iodo-1- [ (4-methoxyphenyl) methyl]A solution of 4-methyl-pyrazole (mixture of regioisomers) (1.34 g, 4.0835mmol) and diisopropylethylamine (1.0685g, 1.44mL, 8.2674mmol) in toluene (25mL) was degassed.Tris (dibenzylideneacetone) dipalladium (0) (111mg, 0.1212mmol), Xantphos (142mg, 0.2454mmol) and 2-ethylhexyl 3-sulfanylpropionate (98 mmol) were added6mg, 4.5156mmol), the vial was sealed and the mixture was heated at 110 ℃ overnight, the reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel chromatography using a gradient of 0% to 20% ethyl acetate in heptane to give 3- [1- [ (4-methoxyphenyl) methyl ] p-henyl as an orange oil ]-4-methyl-pyrazol-3-yl]Sulfanylpropionic acid 2-ethylhexyl ester and 3- [2- [ (4-methoxyphenyl) methyl group]-4-methyl-pyrazol-3-yl]Thioalkyl propionic acid 2-ethylhexyl ester (mixture of regioisomers) (1.54g, 90%). ESI-MS M/z calculated 418.229, Experimental 419.3(M +1)⁺(ii) a Retention time: 2.58min (LC method I).

And step 3: sodium [1- [ (4-methoxyphenyl) methyl ] -4-methyl-pyrazol-3-yl ] sulfinyloxy and sodium [2- [ (4-methoxyphenyl) methyl ] -4-methyl-pyrazol-3-yl ] sulfinyloxy (mixture of regioisomers)

Sodium methoxide (750.17mg, 13.886mmol) was added to 3- [1- [ (4-methoxyphenyl) methyl group at room temperature]-4-methyl-pyrazol-3-yl]Sulfonylpropionic acid 2-ethylhexyl ester and 3- [2- [ (4-methoxyphenyl) methyl group]-4-methyl-pyrazol-3-yl]A solution of 2-ethylhexyl sulfonylpropionate (mixture of regioisomers) (1.56g, 3.4621mmol) in tetrahydrofuran (4mL) and methanol (1.4mL) the reaction mixture was stirred for 2h, then the mixture was concentrated under reduced pressure to give 1- [ (4-methoxyphenyl) methyl ] ethyl acetate as a beige solid]-4-methyl-pyrazol-3-yl]Sodium sulfinyloxy and [2- [ (4-methoxyphenyl) methyl group]-4-methyl-pyrazol-3-yl]Sodium sulfinyloxy (mixture of regioisomers) (1.04g, 104%). ESI-MS M/z calculated 288.0545, Experimental 289.1(M +1) ⁺(ii) a Retention time: 1.5min (LC method I).

And 4, step 4: 1- [ (4-methoxyphenyl) methyl ] -4-methyl-pyrazole-3-sulfonamide and 2- [ (4-methoxyphenyl) methyl ] -4-methyl-pyrazole-3-sulfonamide (mixture of regioisomers)

hydroxylamine-O-sulfonic acid (9.7g, 85.770mmol) was added to [1- [ (4-methoxyphenyl) methyl at 0 deg.C]-4-methyl-pyrazol-3-yl]Sodium sulfinyloxy and [2- [ (4-methoxyphenyl) methyl group]-4-methyl-pyrazol-3-yl]A solution of sodium sulfinyloxy (mixture of regioisomers) (12.4g, 43.011mmol) and sodium acetate (10.5g, 128.00mmol) in water (400mL) the mixture was stirred at room temperature overnight, then extracted with ethyl acetate (2X 300mL), the organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure, the residue was purified by column chromatography on silica eluting with 20% to 60% ethyl acetate/heptane to give 1- [ (4-methoxyphenyl) methyl ] methyl) as an off-white solid]-4-methyl-pyrazole-3-sulfonamide and 2- [ (4-methoxyphenyl) methyl]-4-methyl-pyrazole-3-sulfonamide (mixture of regioisomers) (9.72g, 80%). ESI-MS M/z calculated 281.0834, Experimental 282.1(M +1)⁺(ii) a Retention time: 1.51min (LC method I).

And 5: 4-methyl-1H-pyrazole-3-sulfonamides

1- [ (4-methoxyphenyl) methyl group at 80 DEG C]-4-methyl-pyrazole-3-sulfonamide and 2- [ (4-methoxyphenyl) methyl]A solution of-4-methyl-pyrazole-3-sulfonamide (mixture of regioisomers) (270mg, 0.9597mmol) in trifluoroacetic acid (2mL) was stirred overnight. The mixture was concentrated and the residue was purified by silica gel chromatography using a gradient of 20% -100% ethyl acetate/heptane, followed by isocratic 10% methanol/ethyl acetate to give 4-methyl-1H-pyrazole-3-sulfonamide as a white solid (120mg, 78%).¹H NMR (300MHz, dimethylsulfoxide-d)₆) ppm 2.12(s, 3H), 7.29(s, 2H), 7.64(s, 1H), 13.11(br.s., 1H). ESI-MS M/z calculated 161.0259, Experimental 162.1(M +1)⁺(ii) a Retention time: 0.46min (LC method I).

Step 6: 2, 2-dimethyl-4- [3- (4-methyl-3-sulfamoyl-pyrazol-1-yl) propyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

A solution of tert-butyl 2, 2-dimethyl-4- (3-methylsulfonyloxypropyl) pyrrolidine-1-carboxylate (750 mg, 2.236mmol), potassium carbonate (772mg, 5.586mmol) and 4-methyl-1H-pyrazole-3-sulfonamide (300 mg, 1.861mmol) in N, N-dimethylformamide (3mL) was stirred at 80 ℃ for 4H. The mixture was filtered and dissolved in diethyl ether, the mixture was washed with water, dried over sodium sulfate, filtered and evaporated in vacuo, the residue was purified by silica gel chromatography (0% to 30% ethyl acetate/hexanes) resulting in poor separation, the pooled fractions were combined, evaporated and purified by preparative reverse phase HPLC (C) ₁₈1% -99% acetonitrile/hydrochloric acid modifier in water) to obtain 2, 2-dimethyl-4- [3- (4-methyl-3-sulfamoyl-pyrazol-1-yl) propyl ] as the first main regioisomer to be eluted]Pyrrolidine-1-carboxylic acid tert-butyl ester (200mg, 27%).¹H NMR (400MHz, chloroform-d) 7.23-7.19(m, 1H), 5.06(s, 2H), 4.08(t, J ═ 7.0Hz, 2H), 3.65(dd, J ═ 10.2, 7.6Hz, 1H), 2.82(t, J ═ 10.6Hz, 1H), 2.26(d, J ═ 0.7Hz, 3H), 2.11-1.97(m, 1H), 1.92-1.82(m, 3H), 1.66-1.58(m, 1H), 1.46(s, 9H), 1.39(s, 3H), 1.37-1.30(m, 2H), 1.27(s, 3H). ESI-MS M/z calculated 400.21442, Experimental 401.26(M +1)⁺(ii) a Retention time: 0.65min (LC method A).

And 7: 2-chloro-N- [1- [3- (5, 5-dimethylpyrrolidin-3-yl) propyl ] -4-methyl-pyrazol-3-yl ] sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide (hydrochloride)

The mixture was charged with carbonyldiimidazole (73mg, 0.4502mmol) and 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]A50 mL flask of pyridine-3-carboxylic acid (170mg, 0.4525mmol) was evacuated/backfilled with nitrogen tetrahydrofuran (5mL) was added and the mixture stirred at 50 ℃ for 1h, next, 2-dimethyl was added -4- [3- (4-methyl-3-sulfamoyl-pyrazol-1-yl) propyl]Pyrrolidine-1-carboxylic acid tert-butyl ester (150mg, 0.3745 mmol) and 1, 8-diazabicyclo [5.4.0]A solution of undec-7-ene (143mg, 0.9393mmol) in tetrahydrofuran (4mL) and the mixture was stirred at 50 ℃ overnight the reaction was diluted with ethyl acetate and washed with water the organic phase was dried over sodium sulfate, evaporated in vacuo and purified by preparative reverse phase HPLC (C)₁₈1% -99% acetonitrile/hydrochloric acid modifier in water) to yield the acylsulfonamide intermediate, which was dissolved in dioxane (5 mL) and treated with hydrochloric acid (1.3mL, 6M in dioxane, 7.800mmol), and the mixture was stirred at room temperature for 3 h]-4-methyl-pyrazol-3-yl]Sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (hydrochloride) (57mg, 22%). ESI-MS M/z calculated 657.2112, Experimental 658.32(M +1)⁺(ii) a Retention time: 0.6min (LC method A).

And 8: 12, 20, 20-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7 ]Docosac-2 (7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (compound 199)

In a 5mL vial, 2-chloro-N- [1- [3- (5, 5-dimethylpyrrolidin-3-yl) propyl ] was sealed]-4-methyl-pyrazol-3-yl]Sulfonyl-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (hydrochloride) (57mg, 0.08206mmol), potassium carbonate (58mg, 0.4197mmol), cesium fluoride (25mg, 0.1646 mmol) and

molecular sieves (300mg) and purged with nitrogen dimethyl sulfoxide (3mL) was added and the mixture was stirred at 150 ℃ overnight. The mixture was filtered and purified by preparative reverse phase HPLC (C)₁₈1% -99% acetonitrile/hydrochloric acid modifier in waterPurifying to obtain 12, 20, 20-trimethyl-4- (3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2 (7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (compound 199) (6.2mg, 12%). ESI-MS M/z calculated 621.2345, Experimental 622.35(M +1)⁺(ii) a Retention time: 2.16min (LC method B).

Example 174: preparation of (14S) -8- (3-cyclohexyl-2-oxoimidazolidin-1-yl) -12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 200)

Step 1: (14S) -8- (3-cyclohexyl-2-oxoimidazolidin-1-yl) -12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 200)

A5 mL vial was charged with (14S) -8-chloro-12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (50mg, 0.1075 mmol), 1-cyclohexyl imidazolidin-2-one (26mg, 0.1545mmol), Pd₂(dba)₃(26mg, 0.02839 mmol), Xantphos (16mg, 0.02765mmol), cesium carbonate (180mg, 0.5525mmol) and anhydrous dioxane (800. mu.L). The mixture was aerated with nitrogen for 1-2min, capped and stirred at 120 ℃ for 20h, and then cooled to room temperature. The solvent was evaporated, the reaction diluted with dimethyl sulfoxide (900 μ L), microfiltered and chromatographed by reverse phase preparative chromatography using C₁₈Column (10% -99% acetonitrile in water +5mM hydrochloric acid modifier) And (5) purifying. The product fractions were combined, brine was added and the organic solvent was evaporated. The product is further purified by silica gel chromatography using a gradient of 100% dichloromethane to 5% methanol/dichloromethane to give (14S) -8- (3-cyclohexyl-2-oxoimidazolidin-1-yl) -12, 12-dimethyl-2. lambda. as an off-white solid ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 200) (22.5mg, 36%).¹H NMR (400MHz, chloroform-d) 10.79(s, 1H), 8.01(d, J ═ 8.7Hz, 1H), 7.90(d, J ═ 8.8Hz, 1H), 7.55(q, J ═ 2.9, 2.1Hz, 2H), 6.54(dd, J ═ 5.4, 3.7Hz, 1H), 4.80(s, 1H), 3.99(dd, J ═ 9.1, 7.1Hz, 2H), 3.83(s, 2H), 3.45(t, J ═ 8.1Hz, 2H), 3.32(t, J ═ 8.9Hz, 1H), 3.23-3.10(m, 1H), 3.04(t, J ═ 9.4Hz, 1H), 2.71(s, 1H), 2.12 (s, 12.12H), 6.85 (d, 1.6.1H), 6.6.1H, 1H, 6.6.6, 1H, 6.6.6H, 1H, 6.6H, 1H, 6H, 1H, 6.6H, 6H, 1H, 6H, 1H, 6H, 1H) ESI-MS calculated M/z 581.27844, Experimental 582.2(M +1)⁺(ii) a Retention time: 1.86min (LC method E).

Example 175: preparation of 4- [3- (3, 3-Dicyclopropylpropoxy) -1H-pyrazol-1-yl]-12, 20, 20-trimethyl-10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2 (7), 3, 5, 11(22), 12-pentaen-8, 10, 10-trione (enantiomer 1) (compound 201) and 4- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl ]-12, 20, 20-trimethyl-10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2 (7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 202)

Step 1: 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl ] -N- [1- [3- (5, 5-dimethylpyrrolidin-3-yl) propyl ] -4-methyl-pyrazol-3-yl ] sulfonyl-pyridine-3-carboxamide (hydrochloride)

The mixture containing carbonyldiimidazole (78mg, 0.4810mmol) and 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl]A50 mL flask of pyridine-3-carboxylic acid (174mg, 0.4809mmol) was evacuated/backfilled with nitrogen. Tetrahydrofuran (8mL) was added and the mixture was stirred at 50 ℃ for 1h, then 2, 2-dimethyl-4- [3- (4-methyl-3-sulfamoyl-pyrazol-1-yl) propyl was added]Pyrrolidine-1-carboxylic acid tert-butyl ester (160mg, 0.3995mmol) and 1, 8-diazabicyclo [5.4.0]A solution of undec-7-ene (160mg, 1.051mmol) in tetrahydrofuran (4mL) and the mixture was stirred at 50 ℃ overnight. The reaction was diluted with ethyl acetate and washed with water the organic phase was dried over sodium sulfate, evaporated in vacuo and purified by silica gel chromatography (0% to 50% ethyl acetate/hexanes) to give some pure fractions ₁₈Acetonitrile/hydrochloric acid modifier in water 1% -99%) and combining the resulting pure material with the pure fraction from the initial silica gel column to give the acylsulfonamide intermediate a solution of the acylsulfonamide intermediate in dioxane (5mL) is treated with hydrochloric acid (1.3mL, 6M in dioxane, 7.800mmol) and the mixture is evaporated in vacuo at room temperature for 3h to give 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl]-N- [1- [3- (5, 5-dimethylpyrrolidin-3-yl) propyl ] methyl]-4-methyl-pyrazol-3-yl]Sulfonyl-pyridine-3-carboxamide (hydrochloride) (160mg, 59%). ESI-MS M/z calculated 643.27075, experimental 644.38(M +1)⁺(ii) a Retention time: 0.65min (LC method A).

Step 2: 4- [3- (3, 3-Dicyclopropylpropoxy) -1H-pyrazol-1-yl]-12, 20, 20-trimethyl-10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosal-2 (7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione

In a 5mL vial, 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl is sealed]-N- [1- [3- (5, 5-dimethylpyrrolidin-3-yl) propyl ] methyl]-4-methyl-pyrazol-3-yl]Sulfonyl-pyridine-3-carboxamide (hydrochloride) (160mg, 0.2351mmol), potassium carbonate (165mg, 1.194mmol), cesium fluoride (73mg, 0.4806mmol) and

Molecular sieves (300mg) and purged with nitrogen. Dimethyl sulfoxide (4mL) was added and the mixture was stirred at 150 ℃ overnight. The mixture was filtered and purified by preparative reverse phase HPLC (C)₁₈1% -99% acetonitrile/hydrochloric acid modifier in water) to obtain 4- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl]-12, 20, 20-trimethyl-10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosal-2 (7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (53.7mg, 38%). ESI-MS M/z calculated 607.29407, Experimental 608.41(M +1)⁺(ii) a Retention time: 2.36min (LC method B).

And step 3: 4- [3- (3, 3-Dicyclopropylpropoxy) -1H-pyrazol-1-yl]-12, 20, 20-trimethyl-10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2 (7), 3, 5, 11(22), 12-pentaen-8, 10, 10-trione (enantiomer 1) (compound 201) and 4- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl]-12, 20, 20-trimethyl-10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2 (7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 202)

Chromatography by SFC using ChiralPak AS-3 (150X 2.1mm, 3 μm particle size) and 32% acetonitrile/methanol (90: 10)/68% carbon dioxide mobile phase (0.5mL/min, 6.0min) (1.6mg/mL in EtOHNitrile/methanol (90: 10) solution) on 4- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl]-12, 20, 20-trimethyl-10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]The docosane-2 (7), 3, 5, 11(22), 12-pentaen-8, 10, 10-trione (53.7mg) was subjected to chiral separation to give 4- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl group as the first enantiomer to be eluted]-12, 20, 20-trimethyl-10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2 (7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 1) (compound 201) (3.5mg, 5%). ESI-MS M/z calculated 607.29407, Experimental 608.38(M +1)⁺(ii) a Retention time: 2.36min (LC method B.) the second enantiomer to be eluted is 4- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl]-12, 20, 20-trimethyl-10. lambda⁶-thia-1, 3, 9, 14, 22-pentaazatetracyclo [16.2.1.111, 14.02, 7 ]Docosal-2 (7), 3, 5, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 202) (5.0mg, 7%). ESI-MS M/z calculated 607.29407, Experimental 608.3(M +1)⁺(ii) a Retention time: 2.49min (LC method B).

Example 176: preparation of 8- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl]-12, 12, 18-trimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 1) (compound 203) and 8- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl]-12, 12, 18-trimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 2) (compound 204)

Step 1: 8- [3- (3, 3-Dicyclopropylpropoxy) -1H-pyrazol-1-yl]-12, 12, 18-trimethyl-2 λ⁶-3, 9, 2, 3,11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 1) (compound 203) and 8- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl ]-12, 12, 18-trimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 2) (compound 204)

Para-racemic 8- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl]-12, 12, 18-trimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (76mg) was subjected to chiral SFC chromatography. The following SFC protocol was employed: ChiralPak AS-H (250X 10mm), 5 μm; mobile phase: 38% acetonitrile: methanol (90: 10), 62% carbon dioxide, 70. mu.L of a 16 mg/mL solution in acetonitrile: methanol: dimethylsulfoxide (74: 8: 18), 10mL/min, was injected. The first enantiomer to be eluted is 8- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl as a white solid]-12, 12, 18-trimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 1) (compound 203) (3.5mg, 6%). ESI-MS M/z calculated 633.30975, Experimental 634.4(M +1) ⁺(ii) a Retention time: 1.54min (LC method J). The second enantiomer to be eluted is 8- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl as a white solid]-12, 12, 18-trimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 2) (compound 204) (3.5mg, 6%). ESI-MS M/z calculated 633.30975, experimental 634.4(M +1)⁺(ii) a Retention time: 1.54min (LC method J).

Example 177: preparation of (14)S) -12, 12-dimethyl-8- (2-oxo-3- {3- [1- (trifluoromethyl) cyclopropyl]Propyl } imidazolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 205)

Step 1: 3- [1- (trifluoromethyl) cyclopropyl ] propanal

Des-Martin periodinane (880mg, 2.075mmol) was added to 3- [1- (trifluoromethyl) cyclopropyl under nitrogen at 0 deg.C (ice-water bath)]After 15min of a stirred solution of propan-1-ol (350mg, 1.665mmol) in anhydrous dichloromethane (10mL), the bath was removed and the reaction was allowed to warm to ambient temperature and stirring was continued for an additional 3 h. The reaction was diluted with ether (60mL) and a saturated aqueous solution of sodium bicarbonate (20mL) was added slowly (to slow carbon dioxide evolution). Sodium thiosulfate (10mL) was then added and the mixture was stirred at ambient temperature for 30 min. The layers were separated and the aqueous layer was extracted with ether (2X 20 mL). The combined organics were washed with brine (20mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure (rotary evaporator, pressure set at 300mbar so as not to evaporate slightly volatile products) to give 3- [1- (trifluoromethyl) cyclopropyl as a yellow oil ]Propionaldehyde (250mg, 90%). this material was used in the next reaction without drying to pure material and without further purification.¹H NMR (400MHz, benzene-d)₆)9.15(s，1H)，1.99-1.90(m，2H)，1.52- 1.44(m，2H)，0.68-0.59(m，2H)，0.00(dd，J＝2.5，1.6Hz，2H)。

Step 2: n- [2- [3- [1- (trifluoromethyl) cyclopropyl ] propylamino ] ethyl ] carbamic acid tert-butyl ester

To a stirred solution of tert-butyl N- (2-aminoethyl) carbamate (242mg, 1.510mmol) in dry methanol (7mL) under nitrogen was added 3- [1- (trifluoromethyl) cyclopropyl]Propionaldehyde (250mg, 1.505mmol) in dry methanol (1mL) after stirring the yellow solution at ambient temperature for 1h, it was cooled to 0 ℃ (ice water bath). Subsequently, sodium borohydride (125mg, 3.304mmol) was added slowly in two portions and the mixture was allowed to warm to ambient temperature and stirring was continued for 13h]Propylamino group]Ethyl radical]Tert-butyl carbamate (467mg, 100%) mixed with some bis-adduct this material was used directly in the next step ESI-MS M/z calculated 310.1868, experimental 311.3(M +1) ⁺(ii) a Retention time: 1.17min (LC method B).

And step 3: 1- [3- [1- (trifluoromethyl) cyclopropyl ] propyl ] imidazolidin-2-one

Solid potassium tert-butoxide (275mg, 2.451mmol) was added to crude N- [2- [3- [1- (trifluoromethyl) cyclopropyl under nitrogen]Propylamino group]Ethyl radical]A solution of tert-butyl carbamate (250mg, 0.8055mmol, contaminated with some bis-adduct from the previous step) in anhydrous tetrahydrofuran (10mL) and the reaction mixture was heated at 70 ℃ for 13 h. The reaction was cooled to ambient temperature and the reaction mixture was acidified to pH 4-5 with aqueous hydrochloric acid (2.5mL, 1M, 2.500 mmol). After removal of volatiles under reduced pressure, the aqueous residue was extracted with ethyl acetate (3 × 25 mL.) the combined organics were washed with brine (2 × 20mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography (gradient of 0% to 10% methanol in dichloromethane) to give 1- [3- [1- (trifluoromethyl) cyclopropyl ] as an off-white solid]Propyl radical]Imidazolidin-2-one (72mg, 38％)。¹h NMR (400MHz, benzene-d)₆)5.35(s, 1H), 2.84(t, J ═ 6.8Hz, 2H), 2.54-2.41 (m, 4H), 1.33-1.25(m, 2H), 1.23-1.17(m, 2H), 0.63-0.54(m, 2H), 0.05-0.06 (m, 2H). ESI-MS M/z calculated 236.11365, Experimental 237.1(M +1) ⁺(ii) a Retention time: 0.93min (LC method B).

And 4, step 4: (14S) -12, 12-dimethyl-8- (2-oxo-3- {3- [1- (trifluoromethyl) cyclopropyl]Propyl } imidazolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 205)

Sequentially add (14S) -8-chloro-12, 12-dimethyl-2. lambda. to a 4mL vial⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (50mg, 0.1111mmol), 1- [3- [1- (trifluoromethyl) cyclopropyl]Propyl radical]Imidazolidin-2-one (32mg, 0.1355mmol), cesium carbonate (130mg, 0.3990mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (10mg, 0.01728mmol) (Xantphos), and anhydrous dioxane (1.1mL). Subsequently, Pd was added under nitrogen₂(dba)₃(10mg, 0.01107mmol) and nitrogen was bubbled through the reaction for an additional 2min and the reaction was capped under nitrogen. The mixture was stirred at 115 ℃ for 14 h. The mixture was cooled to ambient temperature and neutralized with glacial acetic acid (50 μ L, 0.8792mmol), the volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.5mL) and filtered through Whatman 0.45 μm PTFE syringe filter sheet the sample was purified using preparative reverse phase HPLC-MS (30% -99% acetonitrile/water (hydrochloric acid as modifier)), the desired product fractions were combined and concentrated under reduced pressure and the residue was dissolved in ethyl acetate (25mL) and washed successively with saturated aqueous sodium bicarbonate solution (2 × 10mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure Condensation to give (14S) -12, 12-dimethyl-8- (2-oxo-3- {3- [1- (trifluoromethyl) cyclopropyl ] as an off-white solid]Propyl } imidazolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 205) (19.0mg, 26%).¹H NMR (400MHz, methanol-d)₄)7.70(d, J ═ 8.5Hz, 1H), 7.53(dd, J ═ 8.5, 7.2Hz, 1H), 7.43(d, J ═ 8.6Hz, 1H), 7.15(dd, J ═ 7.2, 0.8Hz, 1H), 6.65(dd, J ═ 8.5, 0.8Hz, 1H), 4.14-4.07(m, 1H), 4.07-4.02(m, 1H), 4.02-3.95(m, 1H), 3.56-3.45(m, 2H), 3.29-3.19(m, 3H), 3.03(d, J ═ 13.8 Hz, 1H), 2.86(t, J ═ 10.4Hz, 1H), 2.21-2.09(m, 1H), 1H (m, 1H), 3.83 (d, J ═ 13.8 Hz, 1H), 2.86(t, J ═ 10.4Hz, 1H), 2.21-2.09(m, 1H), 3.83 (m, 1H), 3.69, 1H), 3.55H), 3.69 (d, 1H), 1H, 1H), 3.55H), 1H), 3, 1H, 5(m, 5H), and, 1.42(q, J ═ 11.5Hz, 1H), 1.32-1.26(M, 1H), 0.96-0.90(M, 2H), 0.72-0.66(M, 2H), ESI-MS M/z calcd 649.2658, experimental 650.4 (M +1)⁺(ii) a Retention time: 1.92min (LC method B).

Example 178: preparation of (14S) -12, 12-dimethyl-8- (2-oxo-3- {2- [1- (trifluoromethyl) cyclopropyl ]Ethyl } imidazolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 211)

Step 1: 2- [1- (trifluoromethyl) cyclopropyl ] acetaldehyde

Des-Martin periodinane (2.43g, 5.729mmol) was added to 2- [1- (trifluoromethyl) cyclopropyl under nitrogen at 0 deg.C (ice-water bath)]A stirred solution of ethanol (700mg, 4.542mmol) in dry dichloromethane (15 mL). 1After 5min, the bath was removed and the reaction was allowed to warm to ambient temperature and stirring was continued for an additional 3 h. The reaction was diluted with ether (60mL) and a saturated aqueous solution of sodium bicarbonate (20mL) was added slowly (to slow carbon dioxide evolution). Sodium thiosulfate (10mL) was then added and the mixture was stirred at ambient temperature for 30 min. The layers were separated and the aqueous layer was extracted with ether (2X 20 mL). The combined organics were washed with brine (20mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure (at 300mbar to avoid evaporation of slightly volatile products) to obtain 2- [1- (trifluoromethyl) cyclopropyl as crude material]Acetaldehyde (500mg, 72%). due to volatility, it was not further dried or further purified. ¹H NMR (400MHz, benzene-d)₆)9.24(tt，J＝2.3，1.2Hz，1H)，1.77(d，J＝2.4Hz，2H)，0.66-0.59(m，2H)，0.00(qd，J ＝4.4，2.3Hz，2H)。¹⁹F NMR (376MHz, benzene-d)₆)-70.56。

Step 2: n- [2- [2- [1- (trifluoromethyl) cyclopropyl ] ethylamino ] ethyl ] carbamic acid tert-butyl ester

To a stirred solution of tert-butyl N- (2-aminoethyl) carbamate (527mg, 3.289mmol) in dry methanol (15mL) under nitrogen was added 2- [1- (trifluoromethyl) cyclopropyl]A solution of acetaldehyde (500mg, 3.287mmol) in dry methanol (1 mL). After stirring the yellow solution at ambient temperature for 1h, it was cooled to 0 ℃ (ice-water bath) then sodium borohydride (260mg, 6.872mmol) was slowly added in two portions and the mixture was allowed to warm to ambient temperature and stirring was continued for 15h the volatiles were removed under reduced pressure the residue was dissolved in ethyl acetate (30 mL) and washed with a saturated aqueous solution of sodium bicarbonate (2 x 15mL) and brine (15mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give N- [2- [2- [1- (trifluoromethyl) cyclopropyl ] as a yellow oil]Ethyl hydrogen radical]Ethyl radical]Tert-butyl hydrogen carbamate (970mg, 100%). ESI-MS M/z calculated 296.17117, Experimental 297.3(M +1)⁺(ii) a Retention time: 0.79 min (LC method B).

And step 3: 1- [2- [1- (trifluoromethyl) cyclopropyl ] ethyl ] imidazolidin-2-one

Solid potassium tert-butoxide (460mg, 4.099mmol) was added to N- [2- [2- [1- (trifluoromethyl) cyclopropyl]Ethylamino group]Ethyl radical]Tert-butyl carbamate (400mg, 1.350mmol) in anhydrous tetrahydrofuran (20mL) and the heterogeneous reaction mixture was heated at 70 ℃ for 13 h. The reaction mixture was cooled to ambient temperature and acidified with glacial acetic acid (250 μ L, 4.396 mmol). The volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography (0% -10% methanol/dichloromethane gradient) to give 1- [2- [1- (trifluoromethyl) cyclopropyl ] as an off-white solid]Ethyl radical]Imidazolidin-2-one (127mg, 42%).¹H NMR (400MHz, benzene-d)₆)4.99 (s, 1H), 3.35-3.20(m, 2H), 2.71-2.56(m, 4H), 1.70-1.59(m, 2H), 0.86-0.73(m, 2H), 0.46-0.33(m, 2H). ESI-MS M/z calculated 222.09799, Experimental 223.1(M +1)⁺(ii) a Retention time: 0.78min (LC method B).

And 4, step 4: (14S) -12, 12-dimethyl-8- (2-oxo-3- {2- [1- (trifluoromethyl) cyclopropyl]Ethyl } imidazolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 211)

Sequentially add (14S) -8-chloro-12, 12-dimethyl-2. lambda. to a 4mL vial ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (50mg, 0.1111mmol), 1- [2- [1- (trifluoromethyl) cyclopropyl]Ethyl radical]Imidazolidin-2-one (30mg, 0.1350mmol), cesium carbonate (130mg, 0.3990mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylXanthene (10mg, 0.01728mmol) (Xantphos) and anhydrous dioxane (1mL) nitrogen was bubbled through the heterogeneous mixture for 2 min. Subsequently, Pd was added under nitrogen₂(dba)₃(10mg, 0.01107mmol) and nitrogen was bubbled through the mixture for an additional 2min, and then capped under nitrogen the mixture was stirred at 115 ℃ for 14h the mixture was cooled to ambient temperature and then neutralized with glacial acetic acid (50 μ L, 0.8792 mmol). The volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.5mL) and filtered through Whatman 0.45 μm PTFE syringe filter. Purification of the sample using preparative reverse phase HPLC-MS (30% -99% acetonitrile/water (hydrochloric acid as modifier).) the desired product fractions were combined and concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (25mL) and washed with brine (10 mL.) the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a light yellow solid which was further purified by silica gel column chromatography (0% -10% methanol/dichloromethane) to give (14S) -12, 12-dimethyl-8- (2-oxo-3- {2- [1- (trifluoromethyl) cyclopropyl) as an off white solid ]Ethyl } imidazolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 211) (18mg, 25%).¹H NMR (400MHz, methanol-d)₄)7.71(d, J ═ 8.6Hz, 1H), 7.52(dd, J ═ 8.5, 7.2Hz, 1H), 7.42(d, J ═ 8.6Hz, 1H), 7.15(dd, J ═ 7.3, 0.8Hz, 1H), 6.65(d, J ═ 8.5Hz, 1H), 4.17-4.03(m, 2H), 3.99(td, J ═ 10.2, 9.7, 6.7Hz, 1H), 3.53(ddd, J ═ 9.5, 6.9, 2.5Hz, 2H), 3.45-3.37(m, 2H), 3.24(t, J ═ 8.7H [ z, 1H ], 3.03(d, J ═ 13.7, 1H, 3.54, 1H, 3.9, 3.7H, 3.9, 3.5H, 3.9H, 1H, 3, 0.81-0.75(M, 2H). ESI-MS M/z calculated 635.2502, Experimental 636.4 (M +1)⁺(ii) a Retention time: 1.85min (LC method B).

Example 179: preparation of (14S) -8- {3- [ (4, 4-difluorocyclohexyl) methyl]-2-oxoimidazolidin-1-yl } -12, 12-dimethyl-2. lambda⁶-thia3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10% ]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 214)

Step 1: n- [2- [ (4, 4-Difluorocyclohexyl) methylamino ] ethyl ] carbamic acid tert-butyl ester

To a stirred solution of tert-butyl N- (2-aminoethyl) carbamate (325mg, 2.029mmol) in dry methanol (15mL) under nitrogen was added a solution of 4, 4-difluorocyclohexanecarboxaldehyde (300mg, 2.025mmol) in dry methanol (1 mL). After stirring the yellow solution at ambient temperature for 1h, it was cooled to 0 ℃ (ice-water bath) then sodium borohydride (165mg, 4.361mmol) was slowly added in two portions and the mixture was allowed to warm to ambient temperature and stirring was continued for 15h the volatiles were removed under reduced pressure the residue was dissolved in ethyl acetate (30mL) and washed with a saturated aqueous solution of sodium bicarbonate (2 × 15mL) and brine (15mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give N- [2- [ (4, 4-difluorocyclohexyl) methylamino group as a yellow oil]Ethyl radical]Tert-butyl carbamate (590mg, 100%). the crude material was used in the next step without any further purification.¹H NMR (400MHz, benzene-d)₆)4.76(s, 1H), 3.16(q, J ═ 5.8Hz, 2H), 2.35(t, J ═ 5.9Hz, 2H), 2.05(d, J ═ 6.5Hz, 2H), 2.03-1.97(m, 1H), 1.59(s, 9H), 1.54-1.42(m, 4H), 1.16-1.03(m, 2H), 1.02-0.84(m, 1H), 0.48(s, 2H). ESI-MS M/z calculated 292.19623, Experimental 293.3(M +1) ⁺(ii) a Retention time: 0.73min (LC method B).

Step 2: 1- [ (4, 4-Difluorocyclohexyl) methyl ] imidazolidin-2-one

Solid potassium tert-butoxide (866mg, 7.718mmol) was added to N- [2- [ (4, 4-difluorocyclohexyl) methylamino]Ethyl radical]Tert-butyl carbamate (750mg, 2.565mmol) in tetrahydrofuran (12mL) was stirred and the heterogeneous reaction mixture was heated at 70 ℃ for 13 h. Once cooled to room temperature, the reaction mixture was acidified with glacial acetic acid (500. mu.L, 8.792mmol) and concentrated under reduced pressure the residue was partitioned between aqueous sodium bicarbonate (15mL) and ethyl acetate (25mL) and the layers were separated. The combined organics were washed with brine (20mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1- [ (4, 4-difluorocyclohexyl) methyl ] as an off-white solid]Imidazolidin-2-one (379 mg, 68%).¹H NMR (400MHz, methanol-d)₄)3.51-3.44(M, 2H), 3.42-3.35(M, 2H), 3.04(d, J ═ 7.1Hz, 2H), 2.09-1.98(M, 2H), 1.83-1.65(M, 5H), 1.33-1.20(M, 2H), ESI-MS M/z calculated 218.12306, experimental 219.1(M +1)⁺(ii) a Retention time: 0.7min (LC method B).

And step 3: (14S) -8- {3- [ (4, 4-Difluorocyclohexyl) methyl ]-2-oxoimidazolidin-1-yl } -12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 214)

A4 mL vial was charged with (14S) -8-chloro-12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (50mg, 0.1111 mmol), 1- [ (4, 4-difluorocyclohexyl) methyl]Imidazolidin-2-one (34mg, 0.1558mmol), Pd₂(dba)₃(15 mg, 0.01638mmol), xanthphos (16mg, 0.02765mmol), cesium carbonate (213mg, 0.6537 mmol) and anhydrous dioxane (0.75 mL.) the mixture was sparged with nitrogen for about 5min, capped and stirred at 120 ℃ for 22 h. By blowing nitrogen gasThe reaction mixture was concentrated in a vial. The reaction was diluted with dimethylsulfoxide (1.5mL), microfiltered, and subjected to reverse phase preparative HPLC (C) using a gradient of acetonitrile in water (1% to 99%) and hydrochloric acid as a modifier₁₈). The pure fractions were collected and the organic solvent was evaporated the solution was extracted with dichloromethane and the organic phase was dried over sodium sulfate and subsequently filtered. The filtrate was evaporated to give a solid which was purified by flash chromatography on silica gel using a gradient of methanol/dichloromethane (0% to 5%). The residue was triturated with dichloromethane/hexane and the solvent was evaporated to give (14S) -8- {3- [ (4, 4-difluorocyclohexyl) methyl as an off-white solid ]-2-oxoimidazolidin-1-yl } -12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 214) (20mg, 27%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.26(s, 1H), 7.65-7.51(M, 2H), 7.40(d, J ═ 8.6Hz, 1H), 7.03(d, J ═ 7.1Hz, 1H), 6.94 (width d, J ═ 9.1Hz, 1H), 6.69(d, J ═ 8.5Hz, 1H), 4.03-3.85(M, 3H), 3.56-3.40(M, 2H), 3.18-3.03(M, 3H), 2.94(d, J ═ 13.3Hz, 1H), 2.71(d, J ═ 10.9Hz, 1H), 2.12-1.96 (M, 3H), 1.86-1.69(M, 7H), 1.63-1.43(M, 9H), 1.36-1.27(M, 1H), 1.23-1.84 (M, 3H), calculated values of M, 3H), 1.86-1.857H, 1.43(M, 9H), 1.36-1.27(M, 1H), experimental values (M, 1M, 3H, 1M, 3M +1 z/z)⁺(ii) a Retention time: 1.79min (LC method B).

Example 180: preparation of (14S) -12, 12-dimethyl-8- [ 2-oxo-3- (3, 3, 3-trifluoro-2, 2-dimethylpropyl) imidazolidin-1-yl]-2λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 225)

Step 1: 3, 3, 3-trifluoro-2, 2-dimethyl-propanal

Dess-martin periodinane (5.4g, 12.73 mmol) was added to a stirred solution of 3, 3, 3-trifluoro-2, 2-dimethyl-propan-1-ol (2.0g, 75% w/w, 10.55mmol) in anhydrous dichloromethane (30mL) at 0 ℃ (ice water bath) under nitrogen after 15min the bath was removed and the reaction was allowed to warm to ambient temperature and stirring continued for an additional 2 h. The reaction was diluted with ether (80mL) and a saturated aqueous solution of sodium bicarbonate (30mL) was added slowly (to slow carbon dioxide gas evolution) followed by the addition of 10% sodium thiosulfate solution (10mL) and the mixture was stirred at ambient temperature for 30min, all solids dissolved over the time the layers were separated and the aqueous layer was extracted with ether (2X 30 mL.) the combined organics were washed with brine (30mL), dried over anhydrous sodium sulfate, filtered and partially concentrated under reduced pressure to about 3-5mL to give 3, 3, 3-trifluoro-2, 2-dimethyl-propanal (1.37g, 93%) as a crude solution in ether which was used directly in the next step ESI-MS M/z calculated 140.0449, experimental 141.2(M +1) ⁺(ii) a Retention time: 0.42min (LC method E).

Step 2: n- [2- [ (3, 3, 3-trifluoro-2, 2-dimethyl-propyl) amino ] ethyl ] carbamic acid tert-butyl ester

To a stirred solution of tert-butyl N- (2-aminoethyl) carbamate (1.2g, 7.490mmol) in dry methanol (45mL) under nitrogen was added a crude ethereal solution of 3, 3, 3-trifluoro-2, 2-dimethyl-propionaldehyde (1.37g, 9.778mmol) described in the previous step in dry methanol (8 mL). After stirring the pale yellow solution at ambient temperature for 1h, it was cooled to 0 ℃ (ice-water bath) then sodium borohydride (875mg, 23.13mmol) was added slowly in two portions and the mixture was allowed to warm to ambient temperature and stirring was continued for 24 h. The volatiles were removed under reduced pressure the residue was dissolved in ethyl acetate (100mL) and washed with saturated aqueous sodium bicarbonate (2X 50mL) and brine (50mL), sulfuric acidSodium was dried, filtered and concentrated under reduced pressure to give N- [2- [ (3, 3, 3-trifluoro-2, 2-dimethyl-propyl) amino group as a clear viscous oil]Ethyl radical]Tert-butyl carbamate (777mg, 36%). ESI-MS M/z calculated 284.17117, Experimental 285.2(M +1)⁺(ii) a Retention time: 0.97min (LC method E).

And step 3: 1- (3, 3, 3-trifluoro-2, 2-dimethyl-propyl) imidazolidin-2-one

Solid potassium tert-butoxide (860mg, 7.664mmol) was added to N- [2- [ (3, 3, 3-trifluoro-2, 2-dimethyl-propyl) amino]Ethyl radical]Tert-butyl carbamate (777mg, 2.733mmol) in anhydrous tetrahydrofuran (40mL) and the heterogeneous reaction mixture was heated at 70 ℃ for 18 h. The reaction mixture was cooled to ambient temperature and acidified with aqueous hydrochloric acid (1M) to a pH of about 5. The volatiles were removed under reduced pressure and the aqueous residue was extracted with ethyl acetate (3 × 50 mL.) the combined organics were washed with brine (2 × 40mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0% -10% methanol in dichloromethane) to give 1- (3, 3, 3-trifluoro-2, 2-dimethyl-propyl) imidazolidin-2-one as an off-white solid (19.38mg, 3%).¹H NMR (400MHz, chloroform-d) 3.57-3.48(m, 2H), 3.44-3.39(m, 2H), 3.25(d, J ═ 2.5Hz, 2H), 1.16(d, J ═ 5.9Hz, 6H). ESI-MS M/z calculated 210.09799, Experimental 211.1(M +1)⁺(ii) a Retention time: 0.94min (LC method E).

And 4, step 4: (14S) -12, 12-dimethyl-8- [ 2-oxo-3- (3, 3, 3-trifluoro-2, 2-dimethylpropyl) imidazolidin-1-yl]-2λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 225)

A5 mL vial was charged with (14S) -8-chloro-12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (40mg, 0.08890 mmol), 1- (3, 3, 3-trifluoro-2, 2-dimethyl-propyl) imidazolidin-2-one (20.56mg, 0.09781mmol), Pd₂(dba)₃(21.5mg, 0.02348mmol), Xantphos (13.5mg, 0.02333mmol), cesium carbonate (150mg, 0.4604mmol) and anhydrous dioxane (800. mu.L). The mixture was aerated with nitrogen for 1-2min, capped and stirred at 120 ℃ for 20h, and then cooled to room temperature. The solvent was evaporated, the reaction diluted with dimethyl sulfoxide (900 μ L), microfiltered and chromatographed by reverse phase preparative chromatography using C₁₈Column (10% -99% acetonitrile/water +5 mM hydrochloric acid, run over 15 min). The product fractions were combined, brine was added and the organic solvent was evaporated the product was extracted with dichloromethane, the organic phase was dried over sodium sulfate and the solvent was evaporated, yielding a solid. The solid was purified by silica gel chromatography using a gradient of 100% dichloromethane to 5% methanol/dichloromethane the pure fractions were collected and the solvent was evaporated, but impurities still remained. The material was diluted with dimethyl sulfoxide (900 μ L) and chromatographed by reverse phase preparative chromatography using C ₁₈Purification of the column (20% -80% acetonitrile/water +5mM hydrochloric acid run over 30 min) to give (14S) -12, 12-dimethyl-8- [ 2-oxo-3- (3, 3, 3-trifluoro-2, 2-dimethylpropyl) imidazolidin-1-yl as an off-white solid]-2λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 225) (1.9mg, 3%). ESI-MS M/z calculated 623.2502, Experimental 624.2(M +1)⁺(ii) a Retention time: 1.88min (LC method E).

Example 181: preparation of (14S) -8- {3- [ (adamantan-1-yl) methyl]-2-oxoimidazolidin-1-yl } -12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 229)

Step 1: n- [2- (1-adamantylmethylamino) ethyl ] carbamic acid tert-butyl ester

To a stirred solution of tert-butyl N- (2-oxoethyl) carbamate (494mg, 3.103mmol) in anhydrous dichloromethane (20mL) was added a solution of 1-adamantylmethylamine (509mg, 3.080 mmol) in anhydrous dichloromethane (1mL) under nitrogen at ambient temperature followed by glacial acetic acid (200 μ L, 3.517mmol) and the clear reaction stirred for 30min, followed by addition of sodium triacetoxyborohydride (1.0g, 4.718mmol) in one portion at ambient temperature and stirring continued for 13h and removal of volatiles under reduced pressure. The residue was dissolved in ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate (2X 15mL) and brine (15mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give N- [2- (1-adamantylmethylamino) ethyl as a yellow gum ]Tert-butyl carbamate (901mg, 95%). The crude material was used in the next step without further purification. ESI-MS M/z calculated 308.24637, Experimental 309.4(M +1)⁺(ii) a Retention time: 1.09min (LC method B).

Step 2: 1- (1-adamantylmethyl) imidazolidin-2-one

Solid potassium tert-butoxide (520mg, 4.634mmol) was added to N- [2- (1-adamantylmethylamino) ethyl under nitrogen]Tert-butyl carbamate (470mg, 1.524mmol) in a stirred solution of anhydrous tetrahydrofuran (13mL) and the reaction mixture was heated at 70 ℃ for 13 h. The heterogeneous mixture was cooled to ambient temperature and acidified with hydrochloric acid (6.0mL, 1.0M, 6.000mmol) and the volatiles were removed under reduced pressure. The aqueous residue was extracted with ethyl acetate (3 × 10mL) and the combined organics were washed with brine (10mL), dried over anhydrous sodium sulfate, filtered and concentratedConcentrating under reduced pressure. By silica gel chromatography (0% -10% methanol/CH)₂Cl₂) The residue was purified to give 1- (1-adamantylmethyl) imidazolidin-2-one as an off-white solid (49mg, 14%).¹H NMR (400 MHz, benzene-d)₆)5.31(s, 1H), 2.90(dd, J ═ 8.9, 6.6Hz, 2H), 2.83(s, 2H), 2.73(dd, J ═ 8.7, 6.7Hz, 2H), 2.06-1.98(M, 3H), 1.80-1.73(M, 3H), 1.69(dq, J ═ 12.4, 2.3Hz, 3H), 1.61(d, J ═ 2.8Hz, 6H), ESI-MS M/z calculated 234.17322, experimental 235.2(M +1) ⁺(ii) a Retention time: 1.51min (LC method B).

And step 3: (14S) -8- {3- [ (adamantan-1-yl) methyl group]-2-oxoimidazolidin-1-yl } -12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 229)

Sequentially add (14S) -8-chloro-12, 12-dimethyl-2. lambda. to a 4mL vial⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (20mg, 0.04298mmol), 1- (1-adamantylmethyl) imidazolidin-2-one (13mg, 0.05548mmol), cesium carbonate (52mg, 0.1596mmol), xanthphos (4mg, 0.006913mmol), and anhydrous dioxane (1.0 mL). Nitrogen was bubbled through the heterogeneous mixture for 2 min. Subsequently, Pd was added under nitrogen₂(dba)₃(4mg, 0.004368mmol) and nitrogen was bubbled through the reaction mixture for an additional 2min and the mixture was capped under nitrogen. The mixture was stirred at 115 ℃ for 15h the mixture was cooled to ambient temperature and neutralized with glacial acetic acid (20 μ L, 0.3517 mmol). The volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.0mL) and filtered through Whatman 0.45 μm PTFE syringe filter. Purification of the sample using preparative reverse phase HPLC-MS (30% -99% acetonitrile/water (hydrochloric acid as modifier)) gave (14S) -8- {3- [ (adamantan-1-yl) as a yellowish solid Methyl radical]-2-oxoimidazolidin-1-yl } -12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 229) (12mg, 43%). ESI-MS M/z calculated 647.3254, Experimental 648.5 (M +1)⁺(ii) a Retention time: 1.82min (LC method G).

Example 182: preparation of 23, 23-dimethyl-11- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosano-1 (22), 9, 11, 13, 18, 20-hexaene-15, 17, 17-trione (compound 236)

Step 1: 4- (1-methyl-1-nitroethyl) -tetrahydropyran-2-one

Mixing 5, 6-dihydropyran-2-one (50g, 510mmol) and 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene (7.6 mL, 51mmol) was dissolved in 2-nitropropane (138mL, 1530mmol) and the resulting mixture was heated to 100 ℃ under nitrogen for 2.5 h. The reaction was cooled to room temperature and concentrated in vacuo to remove excess volatiles. The remaining oil was dissolved in ethyl acetate (1L) and extracted with 1M hydrochloric acid (100mL) and water (100 mL). The aqueous phase was discarded and the organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to give 4- (1-methyl-1-nitroethyl) -tetrahydropyran-2-one (85g, 79%) as an orange solid ESI-MS M/z calculated 187.00, experimental 188.00(M +1) ⁺(ii) a Retention time: 2.62min (LC method P).

Step 2: 4- (2-hydroxyethyl) -5, 5-dimethylpyrrolidin-2-one

4- (1-methyl-1-nitroethyl) -tetrahydropyran-2-one (85g, 454mmol) was dissolved in ethanol (1.2L), followed by addition of Raney nickel (10g, 170mmol), and the resulting slurry at 2 bar H₂Hydrogenation at 80 ℃ for 25 h. The reaction mixture was filtered, the filter cake discarded, and the filtrate was returned to the reactor and heated to 120 ℃ for 23h⁺(ii) a Retention time: 1.30min (LC method P).

And step 3: 2- (2, 2-dimethylpyrrolidin-3-yl) -ethanol

4- (2-hydroxyethyl) -5, 5-dimethylpyrrolidin-2-one (63.5g, 404mmol) was dissolved in tetrahydrofuran (2L) lithium aluminum hydride (61.3g, 1616mmol) was added in small portions and the resulting slurry was refluxed for 45h under nitrogen, cooled to room temperature and carefully quenched with a saturated solution of sodium sulfate (300 mL). The mixture was diluted with MTBE (1L) and filtered. The filter cake was discarded and the filtrate was dried over sodium sulfate, filtered and concentrated in vacuo to give 2- (2, 2-dimethylpyrrolidin-3-yl) -ethanol (50.8g, 87%) as a pale yellow oil. ESI-MS M/z calculated 143.00, Experimental 144.20(M +1) ⁺(ii) a Retention time: 0.68min (LC method P). The crude product was used without further purification.

And 4, step 4: 3- (2-hydroxyethyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2- (2, 2-Dimethylpyrrolidin-3-yl) -ethanol (50.8g, 355mmol) was dissolved in a mixture of dichloromethane (350mL) and water (350mL) sodium bicarbonate (59.6g, 710mmol) and di-tert-butyl dicarbonate (73.6g, 337mmol) were added and stirred at room temperatureThe resulting mixture was 19 h. Sodium hydroxide (14g, 350mmol) and water (50mL) were then added and the mixture stirred at room temperature for 18h, then diluted with diethyl ether (1L) the phases were separated and the aqueous phase was extracted with diethyl ether (2 x 350mL) the aqueous phase was discarded and the combined organic phases were dried over sodium sulfate, concentrated in vacuo, then triturated with hexanes the resulting pale yellow solid was collected by vacuum filtration to obtain tert-butyl 3- (2-hydroxyethyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate as a pale yellow solid (60.0 g, 69%). ESI-MS M/z calculated 243.00, Experimental 244.00(M +1)⁺(ii) a Retention time: 4.24min (LC method P).

And 5: 3- (2-Methanesulfonyloxyethyl) -2, 2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester

3- (2-hydroxyethyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (54.5g, 224mmol) was dissolved in dichloromethane (545 mL). Triethylamine (62.5mL, 448mmol) was added and the resulting solution was cooled in an ice-water bath, followed by dropwise addition of methanesulfonyl chloride (19.2mL, 247mmol) over a period of 1 h. The phases were separated and the organic phase was extracted with water (2X 200 mL). The aqueous phase was discarded and the organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to give tert-butyl 3- (2-methanesulfonyloxyethyl) -2, 2-dimethylpyrrolidine-1-carboxylate (72.2g, quant) as an orange oil, (ESI-MS calculated M/z 321.00, Experimental 322.20(M +1) ⁺(ii) a Retention time: 5.24min (LC method P).

Step 6: 3- (2-aminoethyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

3- (2-Methanesulfonyloxyethyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (10.0g, 31.1 mmol) was dissolved in1, 4-dioxane (100 mL.) 28% ammonium hydroxide (100mL) was added and the reaction was heated to 40 ℃ in a bayer reactor for 26h. The phases were separated and the aqueous phase was discarded, and the combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo the remaining yellow oil was purified by silica gel chromatography (0% to 15% methanol/dichloromethane gradient) to obtain tert-butyl 3- (2-aminoethyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (5.1g, 68%) as a pale yellow solid, calculated ESI-MS M/z 242.00, experimental 243.20(M +1)⁺(ii) a Retention time: 3.09min (LC method P).

And 7: 2, 2-dimethyl-3- [2- [ (6-sulfamoyl-2-pyridyl) amino ] ethyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

To dimethyl sulfoxide (4.21mL) containing tert-butyl 3- (2-aminoethyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (500mg, 2.063mmol) and 6-fluoropyridine-2-sulfonamide (363.4mg, 2.063mmol) was added potassium carbonate (290.8mg, 2.104mmol) and the mixture was stirred at 100 ℃ for 20h, then allowed to cool to room temperature, diluted with ethyl acetate and poured into NH ₄Cl in saturated aqueous solution. The layers were separated, then the organic layer was washed with saturated brine solution, dried (sodium sulfate), filtered and concentrated to a yellow foam which was purified by silica gel chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate to give 2, 2-dimethyl-3- [2- [ (6-sulfamoyl-2-pyridyl) amino group as a white solid]Ethyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (497.5mg, 61%). ESI-MS M/z calculated 398.19876, Experimental 399.1(M +1)⁺(ii) a Retention time: 0.58min (LC method A).

And 8: 3- [2- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] ethyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxylic acid (499.7 mg, 1.330mmol) and carbonyldiimidazole (269.8mg, 1.664mmol) (recrystallized from tetrahydrofuran) were combined in tetrahydrofuran (6.89mL) and stirred at room temperature for 60min, then, 2-dimethyl-3- [2- [ (6-sulfamoyl-2-pyridyl) amino group was added]Ethyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (530mg, 1.330mmol) in tetrahydrofuran (2.65mL) followed by the addition of 1, 8-diazabicyclo [5.4.0 ]Undec-7-ene (1.013g, 6.654mmol) and the reaction stirred at room temperature for 16 h. Tetrahydrofuran was removed by rotary evaporation and the residue was dissolved in ethyl acetate and washed with 6N hydrochloric acid (1 ×), then brine (1 ×), dried (sodium sulfate), filtered and concentrated to a white solid which was subjected to 275g C eluting with a gradient of 50% -100% acetonitrile/water₁₈Reversed phase column chromatography to obtain white solid 3- [2- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] amino acid]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Ethyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (497.5mg, 49%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.75(s, 1H), 8.40(d, J ═ 2.8Hz, 1H), 8.12(d, J ═ 8.3Hz, 1H), 7.70(d, J ═ 8.3Hz, 1H), 7.62(dd, J ═ 8.5, 7.2Hz, 1H), 7.21(s, 1H), 7.18(d, J ═ 7.2Hz, 1H), 6.74(d, J ═ 8.4Hz, 1H), 6.18(d, J ═ 2.8Hz, 1H), 4.35(t, J ═ 7.1Hz, 2H), 3.25(s, 2H), 3.02(d, J ═ 9.1Hz, 1H), 2.09(t, J ═ 7.1Hz, 2H), 1.90-1.57 (s, 2H), 1.02 (d, J ═ 9.1Hz, 1H), 2.09(t, J ═ 7.1H, 1H), 1H. ESI-MS M/z calculated 755.248, Experimental 756.1(M +1) ⁺(ii) a Retention time: 0.84min (LC method A).

And step 9: 2-chloro-N- [ [6- [2- (2, 2-dimethylpyrrolidin-3-yl) ethylamino ] -2-pyridinyl ] sulfonyl ] -6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide

Reacting 3- [2- [ [6- [ [ 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] group]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Ethyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (498.6mg, 0.6593mmol) was dissolved in dichloromethane (2.176mL) and trifluoroacetic acid (2.032 mL, 26.37mmol) was added to the mixture and the mixture was stirred at room temperature for 60min]-2-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical ]Pyrazol-1-yl]Pyridine-3-carboxamide (351.2mg, 81%). ESI-MS M/z calculated 655.19556, experimental 656.1(M +1)⁺(ii) a Retention time: 0.58min (LC method A).

Step 10: 23, 23-dimethyl-11- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosano-1 (22), 9, 11, 13, 18, 20-hexaene-15, 17, 17-trione (compound 236)

2-chloro-N- [ [6- [2- (2, 2-dimethylpyrrolidin-3-yl) ethylamino ] is used]-2-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (351.2mg, 0.5353mmol), potassium carbonate (369.8mg, 2.676mmol),

Molecular sieves and dimethylsulfoxide (21.3mL)Combine in a vial, purge with nitrogen, cap, heat to 180 ℃ and stir for 18 h. Cooled to room temperature and the mixture was filtered, diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate, followed by brine. The organics were separated, dried over sodium sulfate and evaporated, then purified by silica gel chromatography using a gradient of 100% hexane to 100% ethyl acetate (product eluted after reaching 100% ethyl acetate) to give 23, 23-dimethyl-11- (3- {2- [1- (trifluoromethyl) cyclopropyl ] as a white solid ]Ethoxy } -1H-pyrazol-1-yl) -17 lambda⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosano-1 (22), 9, 11, 13, 18, 20-hexaen-15, 17, 17-trione (compound 236) (5.7mg, 2%). ESI-MS M/z calculated 619.2189, Experimental 620.1(M +1)⁺(ii) a Retention time: 2.08min (LC method B).

Example 183: preparation of (14S) -12, 12-dimethyl-8- (2-oxo-3- { [4- (trifluoromethyl) cyclohexyl]Methyl } imidazolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 239)

Step 1: n- [2- [ [4- (trifluoromethyl) cyclohexyl ] methylamino ] ethyl ] carbamic acid tert-butyl ester

To a stirred solution of 4- (trifluoromethyl) cyclohexanecarboxaldehyde (250mg, 1.388mmol) in dry methanol (10 mL) under nitrogen was added a solution of tert-butyl N- (2-aminoethyl) carbamate (223mg, 1.392mmol) in dry methanol (1 mL). After stirring the yellow solution at ambient temperature for 1h, it was cooled to 0 ℃ (ice-water bath) then sodium borohydride (112mg, 2.960mmol) was slowly added in two portions and the mixture was allowed to warm to ambient temperature and stirring was continued for 15h A hair material. The residue was dissolved in ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate (2 × 15mL) and brine (15mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give N- [2- [ [4- (trifluoromethyl) cyclohexyl ] as a yellow gum]Methylamino radical]Ethyl radical]Tert-butyl carbamate (400mg, 89%). The crude material was used in the next step without further purification. ESI-MS M/z calculated 324.20245, Experimental 325.3(M +1)⁺(ii) a Retention time: 0.9min (LC method B).

Step 2: 1- [ [4- (trifluoromethyl) cyclohexyl ] methyl ] imidazolidin-2-one (cis/trans isomer 2)

Solid potassium tert-butoxide (270mg, 2.406mmol) was added to N- [2- [ [4- (trifluoromethyl) cyclohexyl ] under nitrogen]Methylamino radical]Ethyl radical]Tert-butyl carbamate (260mg, 0.8015mmol) in a stirred solution in anhydrous tetrahydrofuran (10mL) and the reaction mixture was heated at 70 ℃ for 13h. The aqueous residue was extracted with ethyl acetate (3X 10 mL.) the combined organics were washed with brine (10mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC-MS (0% -70% acetonitrile/water (hydrochloric acid as modifier)) to give 1- [ [4- (trifluoromethyl) cyclohexyl ] as an off-white solid as the second cis/trans isomer to be eluted ]Methyl radical]Imidazolidin-2-one (cis/trans isomer 2) (52mg, 26%).¹H NMR (400MHz, benzene-d)₆)4.93(s, 1H), 2.89(d, J ═ 7.2 Hz, 2H), 2.77-2.63(M, 4H), 1.80(dd, J ═ 13.4, 3.6Hz, 2H), 1.72-1.57(M, 1H), 1.52(dd, J ═ 13.4, 3.5Hz, 2H), 1.22-1.06(M, 3H), 0.66(qd, J ═ 13.3, 3.6Hz, 2H), ESI-MS M/z calculated 250.1293, experimental 251.2(M +1)⁺(ii) a Retention time: 1.3min (LC method B).

And step 3: (14S) -12, 12-dimethyl-8- (2-oxo-3- { [4- (trifluoromethyl) cyclohexyl]Methyl }Imidazolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 239)

Sequentially adding (14S) -8-chloro-12, 12-dimethyl-2 lambda to the vial⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (20mg, 0.04445mmol), 1- [ [4- (trifluoromethyl) cyclohexyl]Methyl radical]Imidazolidin-2-one (13mg, 0.05195mmol), cesium carbonate (52mg, 0.1596mmol), Xantphos (4mg, 0.006913mmol), and anhydrous dioxane (0.7 mL). Followed by addition of Pd under nitrogen ₂(dba)₃(4 mg, 0.004368mmol) and nitrogen purged through the mixture for an additional 2min followed by capping under nitrogen stirring the mixture at 108 ℃ for 15h, allowing the mixture to cool to ambient temperature and neutralized with glacial acetic acid (20 μ L, 0.3517 mmol.) the volatiles are removed under reduced pressure and the residue dissolved in dimethyl sulfoxide (1.5mL) and filtered through a Whatman 0.45 μm PTFE syringe filter sheet the sample is purified using preparative reverse phase HPLC-MS (30% -99% acetonitrile/water hydrochloric acid as modifier) to give (14S) -12, 12-dimethyl-8- (2-oxo-3- { [4- (trifluoromethyl) cyclohexyl) as a yellowish solid]Methyl } imidazolidin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 239) (9mg, 31%). this compound is a mono-isomer with unknown cis or trans orientation on the cyclohexane ring.¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.26(s，1H)，7.59(d，J＝ 8.6Hz，1H)，7.58-7.53(m，1H)，7.40(dd，J＝8.6，2.7Hz，1H)，7.06-7.01(m，1H)， 6.94(d，J＝8.7Hz，1H)，6.70(dd，J＝8.5，0.8Hz，1H)，4.01-3.83(m，3H)，3.51- 3.41(m，3H)，3.31-3.28(m，1H)，3.11-3.04(m，2H)，2.94(d，J＝13.4Hz，1H)，2.70 (t，J＝0.8Hz，1H)，2.18(t，J＝8.1Hz，1H)，2.13-2.01(m，1H)，1.95-1.80(m，4H)， 1.79-1.74(m，2H)，1.58(s，3H)，1.57-1.48(m，3H)，1.47(s，3H)，1.34-1.14(m， 3H)，1.00(q，J＝12.6Hz，2H).¹⁹F NMR (376MHz, dimethylsulfoxide-d)₆) -72.24(d, J ═ 8.9 Hz). ESI-MS M/z calculated 663.28143, Experimental 664.4(M +1)⁺(ii) a Retention time: 2.0min (LC method B).

Example 184: preparation of 11- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl ]-7, 7-dimethyl-17. lambda.⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosano-1 (22), 9, 11, 13, 18, 20-hexaene-15, 17, 17-trione (enantiomer 2) (compound 250)

Step 1: 2, 2-dimethyl-4- [2- [ (6-sulfamoyl-2-pyridyl) amino ] ethyl ] pyrrolidine-1-carboxylic acid tert-butyl ester (enantiomer 2)

Separation of racemic 2, 2-dimethyl-4- [2- [ (6-sulfamoyl-2-pyridyl) amino group by chiral SFC using ChiralPak IG (250X 21.2mm column, 5 μm particle size) and 32% methanol (no modifier)/68% carbon dioxide mobile phase (70mL/min)]Ethyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (1.475g, 3.701mmol) gave 2, 2-dimethyl-4- [2- [ (6-sulfamoyl-2-pyridyl) amino as a white foam of the second enantiomer to be eluted]Ethyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (enantiomer 2) (617mg, 84%). ESI-MS M/z calculated 398.19876, Experimental 399.3(M +1)⁺(ii) a Retention time: 1.59min (LC method B).

Step 2: 4- [2- [ [6- [ [ 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] ethyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (enantiomer 2)

To the flask was added 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (147.7 mg, 0.4082mmol), recrystallized carbonyldiimidazole (66.2mg, 0.4083mmol) and tetrahydrofuran (4 mL) the reaction was stirred at 40 ℃ for 90min, followed by addition of 2, 2-dimethyl-4- [2- [ (6-sulfamoyl-2-pyridyl) amino]Ethyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (enantiomer 2) (130mg, 0.3262mmol) followed by addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (150 μ L, 1.003 mmol.) the reaction was stirred overnight the reaction was filtered and purified by HPLC (30% -99% acetonitrile/water + 0.1% hydrochloric acid modifier) to provide 4- [2- [ [6- [ [ 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl ] as a white foam]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Ethyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (enantiomer 2) (64mg, 26%). ESI-MS M/z calculated 741.30756, experimental 742.4(M +1)⁺(ii) a Retention time: 2.19min (LC method G).

And step 3: 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl ] -N- [ [6- [2- (5, 5-dimethylpyrrolidin-3-yl) ethylamino ] -2-pyridinyl ] sulfonyl ] pyridine-3-carboxamide (enantiomer 2)

Adding 4- [2- [ [6- [ [ 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl to the flask]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Ethyl radical]Tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (enantiomer 2) (64mg, 0.08622mmol), dichloromethane (5mL) and trifluoroacetic acid (250 μ L, 3.245 mmol.) the reaction was stirred for 30 min. The reaction was extracted with ethyl acetate, dried over sodium sulfate, filtered and evaporated to afford 2-chloro-6- [3- (3, 3-dicyclopropylpropaxy) as a white solidYl) pyrazol-1-yl]-N- [ [6- [2- (5, 5-dimethylpyrrolidin-3-yl) ethylamino ] amino]-2-pyridyl]Sulfonyl radical]Pyridine-3-carboxamide (enantiomer 2) (51mg, 92%). ESI-MS M/z calculated 641.2551, Experimental value 642.3(M +1)⁺(ii) a Retention time: 1.11min (LC method G).

And 4, step 4: 11- [3- (3, 3-Dicyclopropylpropoxy) -1H-pyrazol-1-yl]-7, 7-dimethyl-17. lambda.⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosano-1 (22), 9, 11, 13, 18, 20-hexaene-15, 17, 17-trione (enantiomer 2) (compound 250)

To a vial were added potassium carbonate (59mg, 0.4269mmol), cesium fluoride (25mg, 0.1646mmol),

Molecular sieves and 2-chloro-6- [3- (3, 3-dicyclopropylpropyloxy) pyrazol-1-yl]-N- [ [6- [2- (5, 5-dimethylpyrrolidin-3-yl) ethylamino ] amino]-2-pyridyl]Sulfonyl radical]Pyridine-3-carboxamide (enantiomer 2) (51mg, 0.07941mmol) in dimethylsulfoxide (3.5 mL.) the reaction was placed in a preheated 150 ℃ oil bath and stirred overnight the reaction was cooled to room temperature, filtered and purified by HPLC (10% -99% acetonitrile/water + 0.1% hydrochloric acid modifier) to give 11- [3- (3, 3-dicyclopropylpropyloxy) -1H-pyrazol-1-yl]-7, 7-dimethyl-17. lambda.⁶-thia-2, 8, 10, 16, 22-pentaazatetracyclo [16.3.1.15, 8.09, 14]Tricosane-1 (22), 9, 11, 13, 18, 20-hexaene-15, 17, 17-trione (enantiomer 2) (compound 250) (14.1mg, 29%). ESI-MS M/z calculated 605.27844, Experimental 606.4(M +1)⁺(ii) a Retention time: 1.9min (LC method G).

Example 185: preparation of (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } -2-oxoethoxy) -1H-pyrazol-1-yl radical]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19 (23)) 20-hexaen-2, 2, 4-trione (Compound 258)

Step 1: 1-dispiro [2.0.2.1] hept-7-yl-2- (1H-pyrazol-3-yloxy) ethanone

Mixing 3- (2-dispiro [2.0.2.1]]Hept-7-yl-2-oxo-ethoxy) pyrazole-1-carboxylic acid tert-butyl ester (350mg, 0.7256mmol) was dissolved in dichloromethane (2.31mL) and trifluoroacetic acid (1.241g, 10.88mmol) and the reaction stirred at room temperature for 60min]Hept-7-yl-2- (1H-pyrazol-3-yloxy) ethanone (223.7mg, 93%). ESI-MS M/z calculated 218.10553, Experimental 219.0(M +1)⁺(ii) a Retention time: 0.43min (LC method A).

Step 2: 2-chloro-6- [3- (2-dispiro [2.0.2.1] hept-7-yl-2-oxo-ethoxy) pyrazol-1-yl ] pyridine-3-carboxylic acid tert-butyl ester

2, 6-dichloropyridine-3-carboxylic acid tert-butyl ester (134.3mg, 0.5413mmol) and 1-dispiro [2.0.2.1]]Hept-7-yl-2- (1H-pyrazol-3-yloxy) ethanone (179.1mg, 0.5416mmol) and potassium carbonate (89.88mg, 0.6503 mmol) were combined in anhydrous dimethylsulfoxide (2.362 mL.) 1, 4-diazabicyclo [2.2.2 ] was added ]Octane (12.16 mg, 0.1084mmol) and the heterogeneous mixture was stirred at room temperature under nitrogen for 16 h. The reaction mixture was diluted with water (4.542mL) and stirred for 15 min. The resulting white solid was collected and washed with water the solid was dissolved in dichloromethane and washed with magnesium sulfateDrying the mixture was filtered and evaporated to give 2-chloro-6- [3- (2-dispiro [2.0.2.1] as a white solid]Hept-7-yl-2-oxo-ethoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid tert-butyl ester (148.7mg, 64%). ESI-MS M/z calculated 429.14554, Experimental value 430.0(M +1)⁺(ii) a Retention time: 0.83min (LC method A).

And step 3: 2-chloro-6- [3- (2-dispiro [2.0.2.1] hept-7-yl-2-oxo-ethoxy) pyrazol-1-yl ] pyridine-3-carboxylic acid

2-chloro-6- [3- (2-dispiro [2.0.2.1]]Hept-7-yl-2-oxo-ethoxy) pyrazol-1-yl]Tert-butyl pyridine-3-carboxylate (145.7mg, 0.3389mmol) was dissolved in dichloromethane (1.457mL) and trifluoroacetic acid (391.7. mu.L, 5.084mmol) and the reaction was stirred at room temperature for 2.5 h. Volatiles were removed by rotary evaporation (no heating) followed by vacuum drying for 30 min. The crude material was purified by silica gel chromatography using a gentle gradient from 100% dichloromethane to 20% methanol/dichloromethane to give 2-chloro-6- [3- (2-dispiro [2.0.2.1] as a brown solid contaminated with a small amount of starting material ]Hept-7-yl-2-oxo-ethoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (89.6mg, 71%) was used directly in the next step. ESI-MS M/z calculated 373.08295, Experimental 374.0 (M +1)⁺(ii) a Retention time: 0.61min (LC method A).

And 4, step 4: (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1] hept-7-yl-2-oxo-ethoxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

2-chloro-6- [3- (2-dispiro [2.0.2.1]]Hept-7-yl-2-oxo-ethoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (89.6mg, 0.2397mmol) and carbonyldiimidazole (48.63mg, 0.2999mmol) (newly recrystallized from tetrahydrofuran) were combined in tetrahydrofuran (1.165mL) and stirred at room temperature for 45minThen, (4S) -2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino group is added]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (98.89mg, 0.2397mmol) in tetrahydrofuran (448. mu.L) followed by the addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (179.3 μ L, 1.199mmol) and the reaction stirred at room temperature for 16 h. The tetrahydrofuran was removed by rotary evaporation, then dissolved in ethyl acetate and washed with 1N hydrochloric acid (1 ×) and brine (1 ×), dried (magnesium sulfate), filtered and concentrated to a light brown oil which was purified by silica gel chromatography using a gentle gradient of 100% dichloromethane to 20% methanol/dichloromethane to give poor separation of the product from the two starting materials ₁₈(2) Column (75 × 30mM, 5 μm particle size) (pn: 00 ℃ -4252-U0-AX) and 15.0min dual gradient run of 1% -99% mobile phase B (mobile phase a ═ water (5mM hydrochloric acid), mobile phase B ═ acetonitrile, flow rate ═ 50mL/min, injection volume ═ 950 μ L, and column temperature ═ 25 ℃), purification to give (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1 ℃.) ]]Hept-7-yl-2-oxo-ethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (49.5mg, 27%). ESI-MS M/z calculated 767.2868, Experimental value 768.1(M +1)⁺(ii) a Retention time: 0.83min (LC method A).

And 5: 2-chloro-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] propylamino ] -2-pyridinyl ] sulfonyl ] -6- [3- (2-dispiro [2.0.2.1] hept-7-yl-2-oxo-ethoxy) pyrazol-1-yl ] pyridine-3-carboxamide (trifluoroacetate)

Mixing (4S) -4- [3- [ [6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1]]Hept-7-yl-2-oxo-ethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (49.5mg, 0.06443mmol) was dissolved in dichloromethane (1.5mL) and cooled to 0 ℃ and trifluoroacetic acid (49.64 μ L, 0.6443mmol) was added dropwise to the mixture and The mixture was stirred at 0 ℃ for 60 min. Trifluoroacetic acid (49.64 μ L, 0.6443mmol) was added dropwise at 0 ℃, followed by warming to room temperature and stirring for 30min, cooling to 0 ℃ again, trifluoroacetic acid (49.64 μ L, 0.6443mmol) was added, warming to room temperature and stirring for 20min, followed by trifluoroacetic acid (49.64 μ L, 0.6443mmol) added dropwise at room temperature and stirring continued for 1h at room temperature. Coevaporation with ether (5X) followed by 1h under vacuum gave 2-chloro-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] as a white solid]Propylamino group]-2-pyridyl]Sulfonyl radical]-6- [3- (2-dispiro [2.0.2.1 ]]Hept-7-yl-2-oxo-ethoxy) pyrazol-1-yl]Pyridine-3-carboxamide (trifluoroacetate) (50.4mg, 100%). ESI-MS M/z calcd for 667.2344, experimental value 668.1 (M +1)⁺(ii) a Retention time: 0.55min (LC method A).

Step 6: (14S) -8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } -2-oxoethoxy) -1H-pyrazol-1-yl radical]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 258)

2-chloro-N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] ester ]Propylamino group]-2-pyridyl]Sulfonyl radical]-6- [3- (2-dispiro [2.0.2.1 ]]Hept-7-yl-2-oxo-ethoxy) pyrazol-1-yl]Pyridine-3-carboxamide (trifluoroacetate) (50.4mg, 0.06443mmol), potassium carbonate (53.43mg, 0.3866mmol),

Molecular sieves and dimethylsulfoxide (3.057mL) were combined in a vial, purged with nitrogen, capped, heated to 155 ℃ and stirred for 18h, cooled to room temperature and the mixture filtered, diluted with ethyl acetate and 1N hydrochloric acid, and the layers were separated, the aqueous layer was washed once more with ethyl acetate, and the organic layers were combined, washed with brine (1 ×), dried (magnesium sulfate), filtered and concentrated to a brown solid, chromatographed on silica gel using 100% hexane toThe solid was purified with a gentle gradient of 100% ethyl acetate to give (14S) -8- [3- (2- { dispiro [2.0.2.1 ] still contaminated with impurities]Hept-7-yl } -2-oxoethoxy) -1H-pyrazol-1-yl radical]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (11 mg). For the subsequent reaction, this material was dissolved in methanol (110 μ L) at room temperature and NaBH was added₄(1.646mg, 0.04351mmol) (vigorous bubbling was noted) and the resulting solution was stirred for 10min, then concentrated by rotary evaporation. The residue was dissolved in dimethyl sulfoxide, filtered and subjected to reverse phase HPLC-MS using Luna C sold by Phenomenex ₁₈(2) Column (75 × 30mM, 5 μm particle size) (pn: 00 ℃ -4252-U0-AX) and dual gradient run over 15.0min of 30% -99% mobile phase B (mobile phase a ═ water (5mM hydrochloric acid), mobile phase B ═ acetonitrile, flow rate ═ 50mL/min, injection volume ═ 950 μ L, and column temperature ═ 25 ℃), purified to give (14S) -8- [3- (2- { dispiro [2.0.2.1 ] —) as starting material recovered in the reduction as a white solid]Hept-7-yl } -2-oxoethoxy) -1H-pyrazol-1-yl radical]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 258) (2.20mg, 20%). ESI-MS M/z calculated 631.2577, Experimental 632.2(M +1)⁺(ii) a Retention time: 1.99min (LC method B).

Example 186: preparation of (14S) -12, 12-dimethyl-8- (2-oxo-3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1, 2-dihydropyridin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 268)

Step 1: 3- [ tert-butyl (dimethyl) silyl ] oxy-1H-pyridin-2-one

3-hydroxy-1H-pyridin-2-one (1g, 9.001mmol) and imidazole (1.6g, 23.50 mmol) were suspended in N, N-dimethylformamide (10mL) under an inert atmosphere. A solution of tert-butyl-chloro-dimethyl-silane (1.5g, 9.952mmol) in N, N-dimethylformamide (10mL) was added dropwise at room temperature over 30 min. Subsequently, the reaction was stirred overnight. The resulting solution was then poured into water and the mixture was extracted with tert-butyl methyl ether (3X 50 mL). The combined organic layers were washed with water, brine and then dried over sodium sulfate. After filtration, the solvent was removed under reduced pressure to give 3- [ tert-butyl (dimethyl) silyl group as a pale brown solid ]oxy-1H-pyridin-2-one (1.8g, 89%) was used directly in the next reaction.¹H NMR (400MHz, chloroform-d) 6.97(ddd, J ═ 6.4, 1.8, 0.8Hz, 1H), 6.89(dd, J ═ 7.2, 1.8Hz, 1H), 6.14(dd, J ═ 7.2, 6.5Hz, 1H), 1.00(d, J ═ 1.3Hz, 9H), 0.26(s, 6H).

Step 2: 2-chloro-6- (3-hydroxy-2-oxo-1-pyridinyl) pyridine-3-carboxylic acid tert-butyl ester

2, 6-dichloropyridine-3-carboxylic acid tert-butyl ester (1g, 4.031mmol), 3- [ tert-butyl (dimethyl) silyl group at room temperature]oxy-1H-pyridin-2-one (910mg, 4.038mmol), potassium carbonate (1.32g, 9.551mmol) and 1, 4-diazabicyclo [2.2.2]A mixture of octane (112mg, 0.9985mmol) in dimethylsulfoxide (10mL) was stirred for 15h the reaction mixture was poured onto crushed ice and the resulting precipitate was collected by filtration and dried to give tert-butyl 2-chloro-6- (3-hydroxy-2-oxo-1-pyridinyl) pyridine-3-carboxylate (0.82g, 63%) as a light brown solid.¹H NMR (400MHz, chloroform-d) 12.57(s, 1H), 8.15(d, J ═ 8.6Hz, 1H), 7.36(dd, J ═ 7.2, 1.8Hz, 1H), 7.23(dd, J ═ 6.6, 1.8Hz, 1H), 6.95(d, J ═ 8.3Hz, 1H), 6.29(t, J ═ 6.9Hz, 1H), 1.59(s, 9H). ESI-MS M/z calculated 322.07202, Experimental 323.14(M +1) ⁺(ii) a Retention time: 0.55min (LC method G).

And step 3: 2-chloro-6- [ 2-oxo-3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] -1-pyridinyl ] pyridine-3-carboxylic acid

Methanesulfonic acid 2- [1- (trifluoromethyl) cyclopropyl at room temperature]A mixture of ethyl ester (362mg, 1.559mmol), tert-butyl 2-chloro-6- (3-hydroxy-2-oxo-1-pyridinyl) pyridine-3-carboxylate (500mg, 1.549mmol), cesium carbonate (1.1g, 3.376mmol) in dimethyl sulfoxide (10mL) was stirred for 15h. The residue was purified by silica gel column chromatography (0% -80% ethyl acetate/hexane) and the second regioisomer to be eluted was separated and trifluoroacetic acid (1.5mL, 19.47 mmol) and dichloromethane (5mL) were added to the material at room temperature with stirring for 2h followed by evaporation of the volatiles to give 2-chloro-6- [ 2-oxo-3- [2- [1- (trifluoromethyl) cyclopropyl ] methyl acetate]Ethoxy radical]-1-pyridinyl]Pyridine-3-carboxylic acid (120mg, 19%).¹H NMR (400MHz, chloroform-d) 8.14(d, J ═ 8.4Hz, 1H), 7.28(td, J ═ 7.2, 1.9Hz, 2H), 6.95(d, J ═ 8.4Hz, 1H), 6.22(t, J ═ 7.1Hz, 1H), 4.13(t, J ═ 7.3Hz, 2H), 2.01(t, J ═ 7.2Hz, 2H), 1.58(s, 9H), 1.01-0.87(M, 2H), 0.69-0.57(M, 2H), ESI-MS M/z 402.05942, experimental 403.13(M +1) ⁺(ii) a Retention time: 0.56min (LC method A).

And 4, step 4: (4S) -4- [3- [ [6- [ [ 2-chloro-6- [ 2-oxo-3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] -1-pyridinyl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

In a 20mL vial, 2-chloro-6- [ 2-oxo-3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]-1-Pyridyl radical]Tert-butyl pyridine-3-carboxylate (100mg, 0.2483mmol) and carbonyldiimidazole (47mg, 0.2899mmol) were combined in tetrahydrofuran (2mL) and stirred at room temperature for 2 h. Followed by addition of (4S) -2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) amino]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (114mg, 0.2763mmol) was added followed by 1, 8-diazabicyclo [5.4.0]Undec-7-ene (50 μ L, 0.3343mmol) and the reaction stirred for 16h the reaction was diluted with ethyl acetate and washed with a small amount of 1: 1 saturated aqueous ammonium chloride solution/brine. The organics were separated, dried over sodium sulfate, filtered and evaporated. The resulting brown residue was purified by silica gel chromatography using a gentle gradient of 100% hexane to 100% ethyl acetate to give (4S) -4- [3- [ [6- [ [ 2-chloro-6- [ 2-oxo-3- [2- [1- (trifluoromethyl) cyclopropyl ] methyl ]Ethoxy radical]-1-pyridinyl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (48mg, 24%). ESI-MS M/z calculated 796.2633, Experimental 797.4(M +1)⁺(ii) a Retention time: 0.81min (LC method A).

And 5: (14S) -12, 12-dimethyl-8- (2-oxo-3- {2- [1- (trifluoromethyl) cyclopropyl]Ethoxy } -1, 2-dihydropyridin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 268)

(4S) -4- [3- [ [6- [ [ 2-chloro-6- [ 2-oxo-3- [2- [1- (trifluoromethyl) cyclopropyl ] at room temperature]Ethoxy radical]-1-pyridinyl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-a solution of tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (48mg, 0.06020mmol) in dichloromethane (400 μ L) and trifluoroacetic acid (100 μ L, 1.307 mmol) was stirred for 4h the solvent was removed by evaporation and dissolved in ethyl acetate this solution was washed with 2 mL of saturated sodium bicarbonate solution and the organic layer was collected and the solvent was removed by evaporation followed by vacuum drying the resulting residue was dissolved in dimethyl sulfoxide (5mL) and added

Molecular sieves and stirring the reaction mixture for 10min then cesium fluoride (36mg, 0.2370mmol) and potassium carbonate (31mg, 0.2243mmol) were added and the reaction mixture was heated at 150 ℃ for 16 h. The reaction mixture was filtered through Whatman filter disc (puradisc 25 TF) and the filtrate was purified by reverse phase HPLC-MS method using a double gradient run of 30% to 99% mobile phase B over 15.0min (mobile phase a ═ water (0.05% hydrochloric acid), mobile phase B ═ acetonitrile) to give (14S) -12, 12-dimethyl-8- (2-oxo-3- {2- [1- (trifluoromethyl) cyclopropyl ] as an off-white solid]Ethoxy } -1, 2-dihydropyridin-1-yl) -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 268) (19.5mg, 49%).¹H NMR (400MHz, chloroform-d) 7.96(d, J ═ 8.4Hz, 1H), 7.59(s, 1H), 7.46(d, J ═ 6.7Hz, 1H), 7.21(t, J ═ 8.4Hz, 2H), 6.72(s, 1H), 6.43(d, J ═ 8.3Hz, 1H), 6.21(t, J ═ 7.0Hz, 1H), 4.06(s, 2H), 3.86(brs, 1H), 3.29-3.13(M, 2H), 2.89(brs, 1H), 2.36(brs, 1H), 1.95(t, J ═ 7.8Hz, 2H), 1.85(brs, 1H), 1.67-1.54(M, 3H), 1.46(t, J ═ 11.84 (t, J ═ 7.8Hz, 2H), experimental calculated values (M, 3H, 1H), 1.67-3H, 11 (M, 1H), experimental values (M, 1H), 1H, 3H), 3H, 19 (M, 1H), 2H, 18H, 1H, 2H, 18H), calculated values (M, 1H, 1 ⁺(ii) a Retention time: 1.83min (LC method B).

Example 187: preparation of 19, 19-dimethyl-4- (3- {3- [1- (trifluoromethyl) cyclopropyl [ ] -]Propoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 21-pentaazatetracyclo [15.2.1.111, 14.02, 7]Heneicosan-2, 4, 6, 11(21), 12-pentaene-8, 10, 10-trione (compound 273)

Step 1: 2, 2-dimethyl-4- (2-methylsulfonyloxyethyl) pyrrolidine-1-carboxylic acid tert-butyl ester

To the flask was added 4- (2-hydroxyethyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (751mg, 3.086 mmol), dichloromethane (10mL) and triethylamine (1.75mL, 12.56 mmol). The reaction flask was cooled to 0 ℃ and then methanesulfonyl chloride (290 μ L, 3.747mmol) was added dropwise and the reaction was allowed to warm to room temperature and stirred for 45min. The reaction was extracted twice with dichloromethane, dried over sodium sulfate, filtered and evaporated to afford tert-butyl 2, 2-dimethyl-4- (2-methylsulfonyloxyethyl) pyrrolidine-1-carboxylate (980mg, 99%) as a thick yellow oil. ESI-MS M/z calculated 321.16098, Experimental 322.1 (M +1)⁺(ii) a Retention time: 1.22min (LC method B).

Step 2: 2, 2-dimethyl-4- [2- (3-sulfamoylpyrazol-1-yl) ethyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

To a 20mL vial was added potassium carbonate (1.264g, 9.146mmol), 1H-pyrazole-3-sulfonamide (449 mg, 3.051mmol) and a solution of tert-butyl 2, 2-dimethyl-4- (2-methylsulfonyloxyethyl) pyrrolidine-1-carboxylate (980mg, 3.049mmol) in N, N-dimethylformamide (12mL) the reaction was capped and placed in a 75 ℃ oil bath and stirred for 18H. The reaction was quenched with brine and extracted 3 times with ethyl acetate the organic layers were combined, dried over sodium sulfate, filtered and evaporated the reaction was purified by column chromatography (0% to 30% methanol/dichloromethane gradient) to give 2, 2-dimethyl-4- [2- (3-sulfamoylpyrazol-1-yl) ethyl ] ethyl as a white solid]Pyrrolidine-1-carboxylic acid tert-butyl ester (259.0mg, 23%) with minor amounts of regioisomeric by-products ESI-MS M/z calculated 372.18314, Experimental 373.2(M +1)⁺(ii) a Retention time: 1.39min (LC method B).

And step 3: 4- [2- [3- [ [ 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] pyrazol-1-yl ] ethyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

The flask was charged with 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] group]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxylic acid (271mg, 0.6953mmol), carbonyldiimidazole (136mg, 0.8387mmol) and tetrahydrofuran (3 mL.) the reaction was placed in a preheated 35 ℃ oil bath and stirred for 2h then the reaction was removed from the oil bath and the solid 2, 2-dimethyl-4- [2- (3-sulfamoylpyrazol-1-yl) ethyl ]Pyrrolidine-1-carboxylic acid tert-butyl ester (259mg, 0.6953mmol) was added to the reaction mixture from a flask flushed with tetrahydrofuran (2mL) 1, 8-diazabicyclo [5.4.0 ] was added]Undec-7-ene (350 μ L, 2.340mmol) and the reaction was stirred at room temperature overnight. The reaction was quenched with brine and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated to provide a foam the foam residue was purified by silica gel chromatography (0% -20% methanol/dichloromethane gradient) to give 4- [2- [3- [ [ 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] as a white foam]Propoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Pyrazol-1-yl]Ethyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (336mg, 65%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)8.35(d, J ═ 2.8Hz, 1H), 8.08(d, J ═ 8.2Hz, 1H), 7.79(s, 1H), 7.62(d, J ═ 8.3Hz, 1H), 6.59(s, 1H), 6.13 (d, J ═ 2.8Hz, 1H), 4.22(t, J ═ 6.2Hz, 2H), 4.13(t, J ═ 7.2Hz, 2H), 3.54(dt, J ═ 23.2, 9.6Hz, 1H), 2.82(t, J ═ 10.5Hz, 1H), 2.00(d, J ═ 8.2Hz, 1H), 1.91-1.78(M, 5H), 1.77-1.68(M, 2H), 1.35 (J ═ 18, J ═ 8.2Hz, 1H), 7.88 (d, J ═ 8.2Hz, 1H), 1H, 1M ═ 3.83-1.84 (M, M ═ 3.3.3, 3.3H), 1.84 (M ═ 3.3.3, 1.3H), 1.3.8 (M ═ 3, 2H), 1.3.8, 1.8, 1H), 1.8, 1.3 ⁺(ii) a Retention time: 1.81min (LC method G).

And 4, step 4: 2-chloro-N- ({1- [2- (5, 5-dimethylpyrrolidin-3-yl) ethyl ] -1H-pyrazol-3-yl } sulfonyl) -6- (3- {3- [1- (trifluoromethyl) cyclopropyl ] propoxy } -1H-pyrazol-1-yl) pyridine-3-carboxamide

Adding 4- [2- [3- [ [ 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] to the flask]Propoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Pyrazol-1-yl]Ethyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (330 mg, 0.4434mmol) and dichloromethane (6 mL). Trifluoroacetic acid (1.5mL, 19.47mmol) was added and the reaction was stirred at room temperature for 1h the reaction was evaporated to dryness, neutralized with saturated sodium bicarbonate and extracted with ethyl acetate (poor solubility in ethyl acetate). The organic layer was dried over sodium sulfate and filtered, most of the desired material was still on the filter cake, so the filter cake (mainly sodium sulfate) was dissolved in water and washed with more ethyl acetate. The organic phase was separated and evaporated without drying over sodium sulfate. The product was dried under vacuum to remove the previous residual water to give 2-chloro-N- ({1- [2- (5, 5-dimethylpyrrolidin-3-yl) ethyl as a white solid]-1H-pyrazol-3-yl } sulfonyl) -6- (3- {3- [1- (trifluoromethyl) cyclopropyl ] sulfonyl ]Propoxy } -1H-pyrazol-1-yl) pyridine-3-carboxamide (246mg, 86%). ESI-MS M/z calculated 643.19556, Experimental 644.3(M +1)⁺(ii) a Retention time: 1.52min (LC method B).

And 5: 19, 19-dimethyl-4- (3- {3- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Propoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 21-pentaazatetracyclo [15.2.1.111, 14.02, 7]Heneicosan-2, 4, 6, 11(21), 12-pentaene-8, 10, 10-trione (compound 273)

To a 20mL vial

Molecular sieves, potassium carbonate (264mg, 1.910mmol), cesium fluoride (116 mg, 0.7636mmol) and 2-chloro-N- ({1- [2- (5, 5-dimethylpyrrolidin-3-yl) ethyl]-1H-pyrazoles-3-yl } sulfonyl) -6- (3- {3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) pyridine-3-carboxamide (246mg, 0.3819mmol) in dimethylsulfoxide (15 mL.) the reaction was capped and placed in a preheated 150 ℃ oil bath and stirred overnight, the reaction was cooled to room temperature, filtered and purified by reverse phase HPLC (10% -99% acetonitrile/water + 0.1% hydrochloric acid modifier) to give 19, 19-dimethyl-4- (3- {3- [1- (trifluoromethyl) cyclopropyl ] carboxamide]Propoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 21-pentaazatetracyclo [15.2.1.111, 14.02, 7 ]Heneicosan-2, 4, 6, 11(21), 12-pentaen-8, 10, 10-trione (compound 273) (25.5mg, 11%). ESI-MS M/z calculated 607.2189, Experimental 608.3(M +1)⁺(ii) a Retention time: 2.08min (LC method B).

Example 188: preparation of 21, 21-dimethyl-4- (3- {3- [1- (trifluoromethyl) cyclopropyl [ ]]Propoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 23-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaene-8, 10, 10-trione (compound 275)

Step 1: 4- [4- [3- [ [ 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] propoxy ] pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] pyrazol-1-yl ] butyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

The flask was charged with 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] group]Propoxy group]Pyrazol-1-yl]Pyridine-3-carboxylic acid (280mg, 0.7184mmol), carbonyldiimidazole (140mg, 0.8634mmol) and tetrahydrofuran (3 mL). The reaction was heated at 35 ℃ for 90 min. The reaction was removed from the oil bath and 2, 2-dimethyl-4- [4- (3-sulfamoylpyrazol-1-yl) butyl was added]A solution of pyrrolidine-1-carboxylic acid tert-butyl ester (288mg, 0.7190mmol) in tetrahydrofuran (3mL) was added followed by 1, 8 -diazabicyclo [5.4.0]Undec-7-ene (350 μ L, 2.340 mmol.) the reaction was stirred for 18h and then quenched with brine and extracted with ethyl acetate the organic layer was dried over sodium sulfate, filtered and evaporated to provide a foam the residual foam was purified by silica gel chromatography (0% -20% methanol/dichloromethane) to give 4- [4- [3- [ [ 2-chloro-6- [3- [1- (trifluoromethyl) cyclopropyl ] 3- [3- [1- (trifluoromethyl) cyclopropyl ] as a white foam]Propoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Pyrazol-1-yl]Butyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (159.1mg, 29%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.88 (s, 1H), 8.39(d, J ═ 2.9Hz, 1H), 8.08(d, J ═ 8.4Hz, 1H), 8.00(d, J ═ 2.4Hz, 1H), 7.69(d, J ═ 8.3Hz, 1H), 6.86(d, J ═ 2.3Hz, 1H), 6.19(d, J ═ 2.9Hz, 1H), 4.23(t, J ═ 6.3Hz, 4H), 3.49(q, J ═ 10.1Hz, 1H), 2.73(q, J ═ 10.0Hz, 1H), 2.07-1.94(M, 1H), 1.82(ddt, J ═ 27.6, 14.2, 7.0, 5H), 1.74-1.69 (H), 2.07-1.70H), 7.70H, 11H, 19 (M, 1H), 11.70H, 19(d, H), 19(d, J ═ 2.3Hz, 1H), 3.3H, 4H, 3.49(q, J ═ 27.6, 14.2, 7.0, 5H, 1H), 11H, 18, 11H, 18H, 19 (M, 11H). ⁺(ii) a Retention time: 1.99min (LC method G).

Step 2: 2-chloro-N- ({1- [4- (5, 5-dimethylpyrrolidin-3-yl) butyl ] -1H-pyrazol-3-yl } sulfonyl) -6- (3- {3- [1- (trifluoromethyl) cyclopropyl ] propoxy } -1H-pyrazol-1-yl) pyridine-3-carboxamide

To a solution containing 4- [4- [3- [ [ 2-chloro-6- [3- [3- [1- (trifluoromethyl) cyclopropyl ] group]Propoxy group]Pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]Pyrazol-1-yl]Butyl radical]To a flask of-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (156mg, 0.2020 mmol) was added dichloromethane (6mL) and trifluoroacetic acid (600 μ L, 7.788mmol), the reaction was stirred at room temperature for 1h, the reaction was evaporated to dryness, and a saturated solution of sodium bicarbonate was added until the reaction mixture pH was 7, ethyl acetate was added and the mixture was stirred for 3 min. The mixture was separated and the organic layer (not completely dissolved) was evaporated to drynessDrying and vacuum drying overnight gave 2-chloro-N- ({1- [4- (5, 5-dimethylpyrrolidin-3-yl) butyl) as a white solid]-1H-pyrazol-3-yl } sulfonyl) -6- (3- {3- [1- (trifluoromethyl) cyclopropyl ] sulfonyl]Propoxy } -1H-pyrazol-1-yl) pyridine-3-carboxamide (133mg, 98%). ESI-MS M/z calculated 671.2268, Experimental 672.4(M +1)⁺(ii) a Retention time: 1.56min (LC method G).

And step 3: 21, 21-dimethyl-4- (3- {3- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Propoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 23-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaene-8, 10, 10-trione (compound 275)

To a vial were added potassium carbonate (137mg, 0.9913mmol), cesium fluoride (62mg, 0.4082mmol),

Molecular sieves and 2-chloro-N- ({1- [4- (5, 5-dimethylpyrrolidin-3-yl) butyl)]-1H-pyrazol-3-yl } sulfonyl) -6- (3- {3- [1- (trifluoromethyl) cyclopropyl ] sulfonyl]Propoxy } -1H-pyrazol-1-yl) pyridine-3-carboxamide (133mg, 0.1979mmol) in dimethylsulfoxide (8mL) the reaction was placed in a preheated 150 ℃ oil bath and stirred for 18H the reaction was filtered and purified by reverse phase HPLC (30% -99% acetonitrile/water + 0.1% hydrochloric acid modifier) to give 21, 21-dimethyl-4- (3- {3- [1- (trifluoromethyl) cyclopropyl ] carboxamide as a white solid]Propoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 23-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaen-8, 10, 10-trione (compound 275) (58.6mg, 47%). ESI-MS M/z calculated 635.2502, Experimental 636.4(M +1) ⁺(ii) a Retention time: 2.22min (LC method B).

Example 189: preparation of 21, 21-dimethyl-4- (3- {3- [1- (trifluoromethyl) cyclopropyl [ ]]Propoxy } -1H-pyrazol-1-yl) -10 lambda⁶Thia-1, 3, 9, 14, 23-pentaazatetracyclo [17.2.1.111, 14.02,7]tricosano-2, 4, 6, 11(23), 12-pentaen-8, 10, 10-trione (enantiomer 1) (compound 276) and 21, 21-dimethyl-4- (3- {3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 23-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 277)

Step 1: 21, 21-dimethyl-4- (3- {3- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Propoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 23-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaen-8, 10, 10-trione (enantiomer 1) (compound 276) and 21, 21-dimethyl-4- (3- {3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 23-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 277)

Racemic 21, 21-dimethyl-4- (3- {3- [1- (trifluoromethyl) cyclopropyl ] 4, 21-dimethyl-by chiral SFC using ChiralPak AS-H (250X 21.2mM column, 5 μm particle size) and a 25% acetonitrile: methanol (90: 10; 20mM NH 3))/75% carbon dioxide mobile phase (10mL/min)]Propoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 23-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaen-8, 10, 10-trione (53mg, 0.08337mmol) was isolated to give 21, 21-dimethyl-4- (3- {3- [1- (trifluoromethyl) cyclopropyl ] as the first enantiomer to be eluted]Propoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 23-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaene-8, 10, 10-trione (p-tridecane-2, 4, 6, 11, 12-pentaene-8, 10-trione)Enantiomer 1) (compound 276) (19.6mg, 74%);¹h NMR (400MHz, dimethylsulfoxide-d)₆)12.57(s, 1H), 8.20(d, J ═ 2.8Hz, 1H), 7.98(s, 1H), 7.75(s, 1H), 6.89 (d, J ═ 9.1Hz, 2H), 6.11(d, J ═ 2.3Hz, 1H), 4.27(s, 2H), 4.20(t, J ═ 6.2Hz, 2H), 2.72(d, J ═ 9.3Hz, 2H), 2.54(s, 6H), 1.85(dd, J ═ 10.3, 5.4Hz, 3H), 1.75-1.69(M, 2H), 1.61(s, 4H), 1.52(s, 4H), 0.93-0.89(M, 2H), 0.77-0.73(M, 2H), ESI-635.2502 (M/z + 84) calculated values from experiments) ⁺(ii) a Retention time: 2.24min (LC method B.) the second enantiomer to be eluted was 21, 21-dimethyl-4- (3- {3- [1- (trifluoromethyl) cyclopropyl ] isomer]Propoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 23-pentaazatetracyclo [17.2.1.111, 14.02, 7]Tricosano-2, 4, 6, 11(23), 12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 277) (16.6mg, 63%). ESI-MS M/z calculated 635.2502, Experimental value 636.4(M +1)⁺(ii) a Retention time: 2.22min (LC method B).

Example 190: preparation of 20, 20, 22-trimethyl-4- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl]-10λ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (atropisomer 2, enantiomer 1) (compound 285) and 20, 20, 22-trimethyl-4- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl]-10λ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (atropisomer 2, enantiomer 2) (compound 286)

Step 1: 20, 20, 22-trimethyl-4- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl ]-10λ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10,10-trione (atropisomer 2, enantiomer 1) (compound 285) and 20, 20, 22-trimethyl-4- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl]-10λ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (atropisomer 2, enantiomer 2) (compound 286)

By chiral SFC, using ChiralPak AS-H (250X 10mM column, 5 μm particle size) and 24% acetonitrile: methanol (90: 10; 20mM NH)₃) /76% carbon dioxide mobile phase (10mL/min) vs. 20, 20, 22-trimethyl-4- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl]-10λ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Dodecan-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (17mg, 0.02788mmol) (rac atropisomer 2) was separated to give 20, 20, 22-trimethyl-4- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl as a yellow solid as the first enantiomer to be eluted ]-10λ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (atropisomer 2, enantiomer 1) (compound 285) (5.4 mg, 64%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.16(bs, 1H), 8.19(d, J ═ 2.8HZ, 1H), 7.81(d, J ═ 7.9HZ, 1H), 7.71(s, 1H), 6.92(d, J ═ 7.9HZ, 1H), 6.10(d, J ═ 2.8HZ, 1H), 4.35(m, 1H), 4.22(bs, 2H), 4.02(m, 1H), 2.66(s, 3H), 2.39(m, 1H), 2.02(m, 3H), 1.83(m, 2H), 1.65(dd, J ═ 12.1HZ, 5.6HZ, 1H), 1.50(q, J ═ 15.6HZ, 12.4HZ, 2H), 1.50(m, 8H), 1.36(q, 6J ═ 12.4HZ, 2H), 1.50(m, 8H), 1.36(q, 6H), 12.6H, 1.6 HZ, 1H), 1.22.6H, 1H, 1.6 HZ, 1H). ESI-MS M/z calculated 609.2345, Experimental 610.4(M +1)⁺(ii) a Retention time: 3.14min (LC method D). The second enantiomer to be eluted is 20, 20, 22-trimethyl isolated as a yellow foam4- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl radical]-10λ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (atropisomer 2, enantiomer 2) (compound 286) (6.5mg, 76%). ESI-MS M/z calculated 609.2345, experimental 610.4(M +1) ⁺(ii) a Retention time: 3.14min (LC method D).

Example 191: preparation of 12, 20, 20-trimethyl-4- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl]-10λ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (enantiomer 1) (compound 290) and 12, 20, 20-trimethyl-4- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl]-10λ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 291)

Step 1: 12, 20, 20-trimethyl-4- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl]-10λ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (enantiomer 1) (compound 290) and 12, 20, 20-trimethyl-4- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl]-10λ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 291)

Using ChiralPak AS-H (250X 21.2mm column, 5 μm particle size) and 20% acetonitrileMethanol (90: 10, 20mM NH)₃) Per 80% carbon dioxide mobile phase (70mL/min) on racemic 12, 20, 20-trimethyl-4- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl]-10λ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Didodec-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (73mg, 0.1197mmol) was subjected to chiral SFC chromatography to give 12, 20, 20-trimethyl-4- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl as the first enantiomer to be eluted]-10λ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (enantiomer 1) (compound 290) (35.1mg, 92%). ESI-MS M/z calculated 609.2345, Experimental 610.4(M +1)⁺(ii) a Retention time: 3.07min (LC method D). the second enantiomer to be eluted was 12, 20, 20-trimethyl-4- [3- (3, 3, 3-trifluoro-2, 2-dimethylpropoxy) -1H-pyrazol-1-yl]-10λ⁶-thia-1, 3, 9, 13, 14-pentaazatetracyclo [16.2.1.111, 14.02, 7]Docosac-2, 4, 6, 11(22), 12-pentaen-8, 10, 10-trione (enantiomer 2) (compound 291) (28.5mg, 78%). ¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.16(bs, 1H), 8.38(s, 1H), 8.19(d, J ═ 2.8Hz, 1H), 7.81(d, J ═ 7.9Hz, 1H), 6.92(d, J ═ 7.9Hz, 1H), 6.10(d, J ═ 2.8Hz, 1H), 4.35(M, 1H), 4.22(bs, 2H), 4.02(M, 1H), 2.38(s, 3H), 2.02(M, 3H), 1.83(M, 2H), 1.75(dd, J ═ 12.1Hz, 5.6Hz, 1H), 1.54(s, 3H), 1.47(s, 3H), 1.36(q, J ═ 15.6Hz, 12.4, 2H), 1.22(s, 6H), 1.84 (ESI, 1.83H), 1.851.84 (M, 1H), calculated values of M + z/M)⁺(ii) a Retention time: 3.07min (LC method D).

Example 192: preparation of 5, 5-dimethyl-9- (3- {2- [1- (trifluoromethyl) cyclopropyl [ ]]Ethoxy } -1H-pyrazol-1-yl) -15 lambda⁶-thia-2, 6, 8, 14, 20-pentaazatetracyclo [14.3.1.13, 6.07, 12]Heneicosan-1 (20), 7, 9, 11, 16, 18-hexaene-13, 15, 15-trione (Compound 31)

Step 1: 1-benzyl-5, 5-dimethyl-pyrrolidin-3-one

To a stirred solution of 5, 5-dimethylpyrrolidin-3-one (1.020g, 9.014mmol) in anhydrous acetonitrile (30mL) at ambient temperature under nitrogen was added anhydrous potassium carbonate (5.00g, 36.18mmol) after stirring for 15min benzyl bromide (1.2mL, 10.09mmol) was added 7h, the reaction mixture was filtered and the filtrate was concentrated in vacuo to provide a crude product, which was extracted from water (20mL) with ethyl acetate (3 × 30mL), the combined organic extracts were washed with water and dried over anhydrous sodium sulfate, filtered through a pad of silica gel and concentrated in vacuo to give the crude product 1-benzyl-5, 5-dimethyl-pyrrolidin-3-one (1.67g, 91%) as an orange viscous mass which was used in the subsequent reaction without further purification. ESI-MS M/z calculated 203.13101, Experimental 204.1(M +1) ⁺(ii) a Retention time: 0.81min (LC method B).

Step 2: (E) -N- (1-benzyl-5, 5-dimethylpyrrolidin-3-ylidene) -2-methylpropane-2-sulfinamide

To a stirred solution of 1-benzyl-5, 5-dimethyl-pyrrolidin-3-one (1.762g, 8.668 mmol) and 2-methylpropane-2-sulfinamide (1.157g, 9.546mmol) in anhydrous tetrahydrofuran (70mL) was added titanium (IV) ethoxide (7.3mL, 34.82mmol) at ambient temperature under nitrogen. The reaction mixture was stirred at 80 ℃ for 13h then allowed to cool to ambient temperature the reaction was quenched slowly with saturated aqueous sodium bicarbonate solution until some precipitate formed (although the titanium salt was white, the salt was light brown due to the product color) (about 40mL of sodium bicarbonate was used)The filter cake was washed after separating the layers from the filtrate, the aqueous portion was extracted with ethyl acetate (2X 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (E) -N- (1-benzyl-5, 5-dimethylpyrrolidin-3-ylidene) -2-methylpropan-2-sulfinamide (2.602 g, 98%) as a light brown solid which was used in the subsequent reaction without further purification ESI-MS M/z calculated 306.17657, experimental 307.2(M +1) ⁺(ii) a Retention time: 0.8min (LC method B).

And step 3: n- (1-benzyl-5, 5-dimethyl-pyrrolidin-3-yl) -2-methyl-propane-2-sulfinamide

To a stirred solution of (E) -N- (1-benzyl-5, 5-dimethylpyrrolidin-3-ylidene) -2-methylpropan-2-sulfinamide (770mg, 2.51mmol) in dry methanol (3mL) and tetrahydrofuran (10mL) at-10 deg.C was added sodium borohydride (290mg, 7.665mmol) in three portions under nitrogen, the reaction was warmed to 0 deg.C and stirred at that temperature for 2h with NH₄The reaction was quenched with aqueous Cl (5mL) followed by saturated aqueous sodium bicarbonate (20mL), the volatiles were removed and the remaining aqueous portion was extracted with ethyl acetate (25mL), and the aqueous layer was extracted with ethyl acetate (2X 15 mL). The combined organic layers were dried (magnesium sulfate), filtered, and concentrated to give crude N- (1-benzyl-5, 5-dimethyl-pyrrolidin-3-yl) -2-methyl-propane-2-sulfinamide (650mg, 84%) as a light brown solid ESI-MS M/z calculated 308.19223, experimental 309.2(M +1)⁺(ii) a Retention time: 0.63min (LC method B).

And 4, step 4: 1-benzyl-5, 5-dimethyl-pyrrolidin-3-amine (dihydrochloride)

Crude N- (1-benzyl-5, 5-dimethyl-pyrrolidin-3-yl) -2-methyl-propane-2-sulfinamide (650mg, 2.107mmol) was dissolved in methanol (10mL) and hydrogen chloride (2.2mL, 4.0M in dioxane, 8.800mmol) was added dropwise at 0 ℃ and the reaction mixture was stirred at room temperature for 1h the volatiles were removed under reduced pressure the trituration with ether was attempted, however, the crude material produced a gummy material, so the ether was removed under reduced pressure and the resulting material was dried under vacuum to give 1-benzyl-5, 5-dimethyl-pyrrolidin-3-amine (dihydrochloride) as a light brown gum (580mg, 99%). ESI-MS M/z calculated 204.16264, Experimental 205.1(M +1)⁺(ii) a Retention time: 0.3min (LC method B).

And 5: 6- [ (1-benzyl-5, 5-dimethyl-pyrrolidin-3-yl) amino ] pyridine-2-sulfonamide

A20 mL vial was charged with 6-fluoropyridine-2-sulfonamide (0.351g, 1.992mmol) and anhydrous dimethyl sulfoxide (5mL), followed by the sequential addition of anhydrous potassium carbonate (1.377g, 9.963mmol) and 1-benzyl-5, 5-dimethyl-pyrrolidin-3-amine (dihydrochloride) (0.580g, 2.092 mmol.) the vial was capped under nitrogen and stirred in an oil bath to 70 ℃ for 13h, followed by stirring at 90 ℃ for 8h, followed by heating approximately at 100 ℃ for about 30min, the reaction mixture was filtered through a pad of celite, followed by dilution with ethyl acetate (30mL) and neutralization with ice AcOH to pH-7, washing with water (15mL), followed by brine (15mL), the organics were dried over sodium sulfate, filtered and evaporated under reduced pressure Gel chromatography purification (0% -15% methanol/dichloromethane) afforded the desired compound, 6- [ (1-benzyl-5, 5-dimethyl-pyrrolidin-3-yl) amino ]Pyridine-2-sulfonamide (125mg, 17%). ESI-MS M/z calculated 360.162, Experimental 361.2(M +1)⁺(ii) a Retention time: 0.59min (LC method B).

Step 6: 6- [ (5, 5-dimethylpyrrolidin-3-yl) amino ] pyridine-2-sulfonamide

Reacting 6- [ (1-benzyl-5, 5-dimethyl-pyrrolidin-3-yl) amino]A stirred solution of pyridine-2-sulfonamide (125mg, 0.3468 mmol) in dry methanol (8mL) was treated with palladium on carbon (40mg, 0.03759mmol) under nitrogen. The reaction was stirred under hydrogen (balloon) at 52 ℃ for 10h, cooled to ambient temperature and the flask evacuated, filled with nitrogen, followed by addition of palladium hydroxide (25mg, 0.03560 mmol.) likewise, the reaction mixture was stirred under hydrogen (balloon) at 52 ℃ for 7h, then allowed to cool to ambient temperature, the catalyst was filtered off over a pad of celite, and the filtrate was concentrated under reduced pressure and dried in vacuo to give 6- [ (5, 5-dimethylpyrrolidin-3-yl) amino group as a light brown solid]Pyridine-2-sulfonamide (61mg, 65%) was used in the next reaction without further purification ESI-MS M/z calculated 270.11505, experimental 271.1(M +1)⁺(ii) a Retention time: 0.53min (LC method B).

And 7: 2-chloro-N- [ [6- [ (5, 5-dimethylpyrrolidin-3-yl) amino ] -2-pyridyl ] sulfonyl ] -6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] ethoxy ] pyrazol-1-yl ] pyridine-3-carboxamide (dihydrochloride)

Reacting 6- [ (5, 5-dimethylpyrrolidin-3-yl) amino]Pyridine-2-sulfonamide (43mg, 0.1591mmol) and carbonyldiimidazole (29mg, 0.1788mmol) were combined in anhydrous tetrahydrofuran (3mL) and stirred at 48 ℃ under nitrogen for 1h, after which 2-chloro-6- [3- [2- [1- (trifluoromethyl) cyclopropyl ] was added]Ethoxy radical]Pyrazol-1-yl]A solution of pyridine-3-carboxylic acid (60mg, 0.1597mmol) in anhydrous tetrahydrofuran (1mL) was added followed by 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene (30 μ L, 0.2006 mmol.) the reaction was removed from heat and stirred at ambient temperature for 12h. volatiles were removed under reduced pressure and the residue was dissolved in dimethyl sulfoxide (1.5mL), filtered through Whatman 0.45 μm PTFE syringe filter and purified by preparative reverse phase HPLC (1% -99% acetonitrile/water, hydrochloric acid as modifier)) Purification to give 2-chloro-N- [ [6- [ (5, 5-dimethylpyrrolidin-3-yl) amino ] as an off-white solid]-2-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]Pyridine-3-carboxamide (dihydrochloride) (13mg, 12%).¹H NMR (400MHz, dimethylsulfoxide-d)₆) 9.09(s, 2H), 8.40(d, J ═ 2.9Hz, 1H), 8.13(d, J ═ 8.3Hz, 1H), 7.77-7.63(M, 3H), 7.23(d, J ═ 7.2Hz, 1H), 6.81(d, J ═ 8.4Hz, 1H), 6.18(d, J ═ 2.9Hz, 1H), 4.45-4.36 (M, 1H), 4.34(t, J ═ 7.1, 2H), 3.72-3.62(M, 1H), 3.26-3.14(M, ddh), 2.24 (M, ddh), 13.4, 8.3Hz, 1H), 2.08(t, J ═ 7.1, 2H), 1.89 (J ═ ddh), 0.92, 0.8.3H, 8.3H, 8.08 (M, 18H), 0.85(M, M ═ 7, 3H, 2H, 3, 8, 3H, 8, 3H, 2.08 (M, 3, M, 3 ⁺(ii) a Retention time: 1.55min (LC method B).

And 8: 5, 5-dimethyl-9- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Ethoxy } -1H-pyrazol-1-yl) -15 lambda⁶-thia-2, 6, 8, 14, 20-pentaazatetracyclo [14.3.1.13, 6.07, 12]Heneicosan-1 (20), 7, 9, 11, 16, 18-hexaene-13, 15, 15-trione (Compound 31)

To 2-chloro-N- [ [6- [ (5, 5-dimethylpyrrolidin-3-yl) amino]-2-pyridyl]Sulfonyl radical]-6- [3- [2- [1- (trifluoromethyl) cyclopropyl]Ethoxy radical]Pyrazol-1-yl]To a solution of pyridine-3-carboxamide (dihydrochloride) (11 mg, 0.01569mmol) in anhydrous dimethylsulfoxide (1.5mL) was added cesium fluoride (3mg, 0.01975mmol), potassium carbonate (12mg, 0.08683mmol) (powderized by mortar and pestle) and a small amount of particulate

Molecular sieves (ca 500mg, heated with a heat gun under vacuum for 5min for drying), the resulting mixture was capped under nitrogen and heated at 150 ℃ for 17h, then allowed to cool to ambient temperature to allow the solids to settle to the bottom, the supernatant was filtered through a Whatman 0.45 μm PTFE syringe filter. The filtrate was concentrated and subjected to reverse phase HPLC-MS using Luna C₁₈(2) Column and double gradient run of 1% -99% acetonitrile/water (no modifier) to purify to obtain 5, 5-dimethyl-9- (3- {2- [1- (trifluoromethyl) cyclopropyl ] methyl acetate ]Ethoxy } -1H-pyrazol-1-yl) -15 lambda⁶-thia-2, 6, 8, 14, 20-pentaazatetracyclo [14.3.1.13, 6.07, 12]Heneicosan-1 (20), 7, 9, 11, 16, 18-hexaen-13, 15, 15-trione (compound 31) (3.5mg, 37%). ESI-MS M/z calculated 591.18756, Experimental 592.3(M +1)⁺(ii) a Retention time: 1.6min (LC method B).

Example 193: preparation of (14S) -12, 12-dimethyl-8- { 3-oxo-octahydroimidazo [1, 5-a ]]Pyridin-2-yl } -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 213)

Step 1: (14S) -12, 12-dimethyl-8- { 3-oxo-octahydroimidazo [1, 5-a ]]Pyridin-2-yl } -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 213)

A5 mL vial was charged with (14S) -8-chloro-12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1- (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (100mg, 0.2222 mmol), 2, 5, 6, 7, 8, 8 a-hexahydro-1H-imidazo [1, 5-a ] ]Pyridin-3-one (45mg, 0.3210mmol), Pd₂(dba)₃(54mg, 0.05897mmol), Xantphos (33mg, 0.05703mmol), cesium carbonate (375 mg, 1.151mmol) and anhydrous dioxane (1.6 mL.) the mixture was aerated with nitrogen for 1-2min, capped and stirred at 120 ℃ for 20h, and then cooledTo room temperature the solvent was evaporated and the reaction was diluted with dimethyl sulfoxide (900 μ L), microfiltered and chromatographed by reverse phase preparative chromatography using C₁₈Column (10% -99% acetonitrile/water +5 mM hydrochloric acid) purification the product fractions were combined, brine was added and the organic solvent was evaporated extraction of the product with dichloromethane, the organic phase was dried over sodium sulfate, filtered and the solvent was evaporated, yielding a solid which was purified by silica gel chromatography using a gradient of 100% dichloromethane to 5% methanol/dichloromethane to give (14S) -12, 12-dimethyl-8- { 3-oxo-octahydroimidazo [1, 5-a ]]Pyridin-2-yl } -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5(10), 6, 8, 19, 21-hexaen-2, 2, 4-trione (compound 213) (58.6mg, 47%).¹H NMR (400MHz, chloroform-d) 10.77(s, 1H), 8.01(d, J ═ 8.7Hz, 1H), 7.90(d, J ═ 8.7Hz, 1H), 7.61-7.49(m, 2H), 6.54(p, J ═ 3.7Hz, 1H), 4.79(d, J ═ 7.9Hz, 1H), 4.21-4.07(m, 1H), 4.02(dd, J ═ 12.5, 3.6Hz, 1H), 3.83(s, 1H), 3.64-3.48 (m, 2H), 3.32(t, J ═ 8.9Hz, 1H), 3.15(d, J ═ 14.0Hz, 1H), 3.04(t, J ═ 9.4, 1H), 2.83 (t, 2H), 1.7 (m, 2H), 1H), 3.5 (d, 1H), 3.55H, 7(d, 1H), 3.5 (d, 2H, 1H), 3.7 (d, 1H), 3H) 1.37(t, J ═ 12.8Hz, 2H.) ESI-MS M/z calculated 553.24713, experimental 554.2(M +1) ⁺(ii) a Retention time: 1.62min (LC method E).

Example 194: preparation of (14S) -12, 12-dimethyl-8- { 1-oxo-2-azaspiro [4.5 ]]Dec-2-yl } -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 222)

Step 1: (14S) -12, 12-dimethyl-8- { 1-oxo-2-azaspiro [4.5 ]]Dec-2-yl } -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 222)

A5 mL vial was charged with (14S) -8-chloro-12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracos-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (50mg, 0.1111 mmol), 2-azaspiro [4.5 ]]Decan-1-one (24mg, 0.1566mmol), Pd₂(dba)₃(26mg, 0.02839 mmol), xanthphos (16mg, 0.02765mmol), cesium carbonate (180mg, 0.5525mmol) and anhydrous dioxane (800 μ L.) the mixture was aerated with nitrogen for 1-2min, capped and stirred at 120 ℃ for 20h, and then cooled to room temperature. The solvent was evaporated, the reaction diluted with dimethyl sulfoxide (900 μ L), microfiltered and chromatographed by reverse phase preparative chromatography using C ₁₈Column (10% -99% acetonitrile/water +5mM hydrochloric acid). The product fractions were combined, brine was added and the organic solvent was evaporated the product was extracted with dichloromethane, the organic phase was dried over sodium sulfate, filtered and the solvent was evaporated to give a solid the solid obtained was purified by silica gel chromatography using a gradient of 100% dichloromethane to 5% methanol/dichloromethane the pure fractions were collected and the solvent was evaporated to give (14S) -12, 12-dimethyl-8- { 1-oxo-2-azaspiro [4.5 ] as an off white solid]Dec-2-yl } -2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 222) (13.01mg, 20%).¹H NMR (400MHz, chloroform-d) 10.41(s, 1H), 8.10-7.95(m, 2H), 7.62-7.49(m, 2H), 6.55(dd, J ═ 6.8, 2.4Hz, 1H), 4.74(s, 1H), 3.93(t, J ═ 7.2Hz, 2H), 3.90-3.79(m, 1H), 3.32(dd, J ═ 10.0, 7.7Hz, 1H), 3.16 (d, J ═ 14.3Hz, 1H), 3.07(s, 1H), 2.68(dd, J ═ 11.9, 6.4Hz, 1H), 2.11(dd, J ═ 12.4, 8.4Hz, 1H), 2.03(dd, J ═ 8.0, 6.4H, 1H), 1H, 2.6.9, 6.4Hz, 1H), 2.11(dd, J ═ 12.4, 8.4Hz, 1H), 2.03(dd, 1H), 1H, 8.0, 1H, 1 (M, 1H), 0.91-0.79 (M, 2H). ESI-MS M/z calculated 566.2675, Experimental 567.2(M +1)⁺(ii) a Retention time: 2.01min (LC method E).

Example 195: preparation of 8- [3- (3, 3-dimethylbutyl) -2-oxoimidazolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracosane-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (compound 232)

Step 1: 2, 6-dichloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-2-yl) propylamino ] -2-pyridinyl ] sulfonyl ] pyridine-3-carboxamide (hydrochloride)

A50 mL flask charged with 2, 6-dichloropyridine-3-carboxylic acid (733mg, 3.818mmol) and carbonyldiimidazole (620mg, 3.824mmol) was evacuated/backfilled with nitrogen. Tetrahydrofuran (15mL) was added and the mixture was stirred at 50 ℃ for 1h, followed by the addition of 2, 2-dimethyl-5- [3- [ (6-sulfamoyl-2-pyridyl) amino]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (1.5g, 3.636mmol) and 1, 8-diazabicyclo [5.4.0]A solution of undec-7-ene (1385 mg, 9.098mmol) in tetrahydrofuran (10mL) and the mixture was stirred at 50 ℃ overnight. The organic phase was dried over sodium sulfate, filtered and evaporated in vacuo, followed by preparative reverse phase chromatography using C ₁₈A solution of this intermediate in dioxane (5mL) was treated with hydrochloric acid (6mL, 6M in dioxane, 36.00mmol) and stirred at room temperature for 3 h. The mixture was evaporated in vacuo to give 2, 6-dichloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-2-yl) propylamino group]-2-pyridyl]Sulfonyl radical]Pyridine-3-carboxamide (hydrochloride) (0.9g, 47%). ESI-MS M/z calculated 485.10553, Experimental 486.15(M +1)⁺(ii) a Retention time: 0.42min (LC method A).

Step 2: 8-chloro-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracosane-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione

In a 5mL vial, potassium carbonate (133mg, 0.9623mmol), cesium fluoride (60mg, 0.3950 mmol) and

molecular sieves (300mg) and purged with nitrogen Next, 2, 6-dichloro-N- [ [6- [3- (5, 5-dimethylpyrrolidin-2-yl) propylamino ] was added]-2-pyridyl]Sulfonyl radical]A solution of pyridine-3-carboxamide (hydrochloride) (100mg, 0.1912mmol) in dimethyl sulfoxide (3mL) and the mixture was stirred at 150 ℃ overnight the mixture was filtered and purified by preparative reverse phase HPLC (C) ₁₈Column, 1% -99% acetonitrile/water + hydrochloric acid modifier) to obtain 8-chloro-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracosan-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (20.8mg, 24%). ESI-MS M/z calculated 449.12885, experimental 450.18(M +1)⁺(ii) a Retention time: 1.46min (LC method B).

And step 3: 8- [3- (3, 3-dimethylbutyl) -2-oxoimidazolidin-1-yl radical]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracosane-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (compound 232)

Reacting 8-chloro-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracosan-1 (23), 5, 7, 9, 20(24) 21-hexaen-2, 2, 4-trione (200mg, 0.4445mmol), 1- (3, 3-dimethylbutyl) imidazolidin-2-one (114mg, 0.6696mmol), Xantphos (65mg, 0.1123mmol), Pd₂(dba)₃A solution of (102mg, 0.1114mmol) and cesium carbonate (724mg, 2.222mmol) in dioxane (4mL) was degassed by purging with nitrogen for 2 min. The mixture was stirred at 120 ℃ overnight. The reaction mixture was filtered and passed through preparative reverse phase HPLC (C) ₁₈Column, 1% -99% acetonitrile/water + hydrochloric acid modifier) to obtain 8- [3- (3, 3-dimethylbutyl) -2-oxoimidazolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 19, 24-pentaazatetracyclo [18.3.1.05, 10.011, 15 [ ]]Tetracosane-1 (23), 5, 7, 9, 20(24), 21-hexaen-2, 2, 4-trione (compound 232) (9mg, 3%). ESI-MS M/z calculated 583.29407, Experimental 584.39 (M +1)⁺(ii) a Retention time: 1.71min (LC method B).

Example 196: preparation of 19, 19-dimethyl-4- (3- {3- [1- (trifluoromethyl) cyclopropyl [ ] -]Propoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 21-pentaazatetracyclo [15.2.1.111, 14.02, 7]Heneicosan-2, 4, 6, 11(21), 12-pentaene-8, 10, 10-trione (enantiomer 1) (compound 279) and 19, 19-dimethyl-4- (3- {3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 21-pentaazatetracyclo [15.2.1.111, 14.02, 7]Heneicosan-2, 4, 6, 11(21), 12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 278)

Step 1: 19, 19-dimethyl-4- (3- {3- [1- (trifluoromethyl) cyclopropyl ] methyl ester]Propoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 21-pentaazatetracyclo [15.2.1.111, 14.02, 7 ]Heneicosan-2, 4, 6, 11(21), 12-pentaene-8, 10, 10-trione (enantiomer 1) (compound 279) and 19, 19-dimethyl-4- (3- {3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 21-pentaazatetracyclo [15.2.1.111,14.02，7]heneicosan-2, 4, 6, 11(21), 12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 278)

ChiralPak AS-H (250X 21.2mM column, 5 μm particle size) and 25% acetonitrile/methanol (90: 10, 20mM NH) were used₃) Per 75% carbon dioxide mobile phase (10mL/min) to racemic 19, 19-dimethyl-4- (3- {3- [1- (trifluoromethyl) cyclopropyl]Propoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 21-pentaazatetracyclo [15.2.1.111, 14.02, 7]Chiral SFC chromatography of heneicosyl-2, 4, 6, 11(21), 12-pentaen-8, 10, 10-trione (21mg, 0.03456mmol) gave 19, 19-dimethyl-4- (3- {3- [1- (trifluoromethyl) cyclopropyl ] ketone as the first enantiomer to be eluted]Propoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 21-pentaazatetracyclo [15.2.1.111, 14.02, 7]Heneicosan-2, 4, 6, 11(21), 12-pentaene-8, 10, 10-trione (enantiomer 1) (compound 279) (7.3mg, 70%). ¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.61(s, 1H), 8.18(d, J ═ 2.7Hz, 1H), 8.01(s, 1H), 7.65(d, J ═ 8.2Hz, 1H), 6.93(s, 1H), 6.85(d, J ═ 8.2Hz, 1H), 6.09(d, J ═ 2.7Hz, 1H), 4.59(d, J ═ 13.9 Hz, 1H), 4.23-4.08(M, 3H), 3.06(s, 1H), 2.17(d, J ═ 14.9Hz, 1H), 1.94(dd, J ═ 11.9, 5.7Hz, 1H), 1.85(dq, J ═ 10.7, 6.3, 2H), 1.77-1.65(M, 3H), 1.56.56 (s, 3H), 1.88 (s, 3H), 0.84 (M, M-0.850, M, 0.83-19H), 0.850 (M, 3H), 1.79 (M, M-19/M, 3H), calculated values (M, 1H), 1H, 5, 1H, 1⁺(ii) a Retention time: 2.08min (LC method B) the second enantiomer to be eluted was 19, 19-dimethyl-4- (3- {3- [1- (trifluoromethyl) cyclopropyl ] methyl]Propoxy } -1H-pyrazol-1-yl) -10 lambda⁶-thia-1, 3, 9, 14, 21-pentaazatetracyclo [15.2.1.111, 14.02, 7]Heneicosan-2, 4, 6, 11(21), 12-pentaene-8, 10, 10-trione (enantiomer 2) (compound 278) (7.8mg, 70%). ESI-MS M/z calculated 607.2189, Experimental 608.4(M +1)⁺(ii) a Retention time: 2.08min (LC formula)Method B).

Example 197: preparation of (14S) -8- [3- (3, 3-dimethylbutyl) -2-oxoimidazolidin-1-yl]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 128)

Step 1: (14S) -8- [3- (3, 3-dimethylbutyl) -2-oxoimidazolidin-1-yl radical]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 128)

Vials were charged with (14S) -8-chloro-12, 12-dimethyl-2. lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (23), 5, 7, 9, 19, 21-hexaen-2, 2, 4-trione (25mg, 0.05373 mmol), 1- (3, 3-dimethylbutyl) imidazolidin-2-one (13mg, 0.07636mmol), Pd₂(dba)₃(13mg, 0.01420mmol), Xantphos (8mg, 0.01383mmol), cesium carbonate (88mg, 0.2701mmol) and anhydrous dioxane (400 μ L) the mixture was aerated with nitrogen for 1-2min, capped and stirred at 120 ℃ for 5 to 14h (heat failure at unknown time during 14h period) the solvent was evaporated, the reaction was diluted with dimethyl sulfoxide (900 μ L), microfiltered and subjected to reverse phase preparative HPLC using a gradient of acetonitrile/water (1% to 99%) and hydrochloric acid as modifier (C) and concentrated solution of acetone₁₈) LCMS of preparative HPLC showed partial conversion (about 20%) to the expected product, which was collected and combined with the product from the second reaction described below.

The second reaction was also carried out using the same amount of reactants and stirred at 120 ℃ for 19hSulfone (1mL) and preparative HPLC (C) on reverse phase using a gradient of acetonitrile/water (1% to 99%) and hydrochloric acid as modifier₁₈) The mixture is purified. The pure fractions were combined with those of the first experiment, a little brine was added and the organic solvent was evaporated the product was extracted with dichloromethane and the organic phase was dried over sodium sulfate filtered, followed by evaporation of the solvent to yield a solid the solid residue was purified by silica gel flash chromatography using a gradient of methanol/dichloromethane (0% to 5%) to give (14S) -8- [3- (3, 3-dimethylbutyl) -2-oxoimidazolidin-1-yl as an off-white solid]-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 128) (17mg, 27%).¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.29(s, 1H), 7.62-7.52(m, 2H), 7.41(d, J ═ 8.6Hz, 1H), 7.03(d, J ═ 7.2Hz, 1H), 6.95 (width d, J ═ 9.0Hz, 1H), 6.69(d, J ═ 8.5Hz, 1H), 4.01-3.80(m, 3H), 3.53-3.40(m, 2H), 3.21(dd, J ═ 10.1, 6.1Hz, 2H), 3.12-3.03(m, 1H), 2.93(d, J ═ 13.4Hz, 1H), 2.76-2.62(m, 1H), 2.08 (br, 1H), 1.85-1.68(m, 2H), 1.64-1.64 (m, 1H), 1.11, 11.92 (m, 1H), 1H (m, 9H), 1H). ESI-MS M/z calculated 583.29407, Experimental 584.4(M +1) ⁺(ii) a Retention time: 1.88min (LC method B).

Example 198: preparation of (14S) -8- (3, 4-dihydro-2H-pyran-6-yl) -12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 303)

Step 1: 2-chloro-6- (3, 4-dihydro-2H-pyran-6-yl) pyridine-3-carboxylic acid tert-butyl ester

A50 mL round bottom flask equipped with a magnetic stir bar was charged with tert-butyl 2, 6-dichloropyridine-3-carboxylate (10.09g, 40.668mmol), 2- (3, 4-dihydro-2H-pyran-6-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxoborole (10.55g, 49.215mmol), and Pd (PPh) in EtOH (10mL), toluene (10mL), and water (2mL)₃)₂Cl₂(1.42g, 2.0231 mmol). The mixture was refluxed at 95 ℃ overnight in an oil bath. The cooled reaction was concentrated, then dissolved in ethyl acetate and washed with brine solution. The organic layer was dried over sodium sulfate, filtered and evaporated to give a crude oil which was purified by silica gel chromatography using a gradient of 100% hexane to 5% ethyl acetate/hexane to provide tert-butyl 2-chloro-6- (3, 4-dihydro-2H-pyran-6-yl) pyridine-3-carboxylate (9.2g, 76%) as a colorless oil. ¹H NMR (250MHz, dimethylsulfoxide-d)₆)8.17(d, J ═ 8.0Hz, 1H), 7.53(d, J ═ 8.0Hz, 1H), 6.19-6.04(M, 1H), 4.27-4.06 (M, 2H), 2.23(q, J ═ 6.1, 4.4Hz, 2H), 1.96-1.78(M, 2H), 1.55(s, 9H), ESI-MS M/z calculated value 295.09753, experimental value 296.0(M +1)⁺(ii) a Retention time: 6.52min (LC method Q).

Step 2: 2-chloro-6- (3, 4-dihydro-2H-pyran-6-yl) pyridine-3-carboxylic acid

Lithium hydroxide monohydrate (468mg, 11.153mmol) was added to a solution of tert-butyl 2-chloro-6- (3, 4-dihydro-2H-pyran-6-yl) pyridine-3-carboxylate (320mg, 1.0711mmol) in methanol (5mL), tetrahydrofuran (20mL) and water (10 mL.) the mixture was stirred at 40 ℃ for 16H and cooled to room temperature, the mixture was acidified with 5% HCl and extracted with EtOAc (2 × 20 mL.) the combined organic layers were washed with brine and washed with Na₂SO₄Drying, filtration and evaporation gave 2-chloro-6- (3, 4-dihydro-2H-pyran-6-yl) pyridine-3-carboxylic acid (248mg, 94%) as a white solid.¹H NMR(250MHz，DMSO-d₆)8.25(d，J＝ 8.0Hz，1H)，7.55(d，J＝8.0Hz，1H)，613(t, J ═ 4.2Hz, 1H), 4.21-4.12(M, 2H), 2.24(q, J ═ 6.3, 5.8Hz, 2H), 1.86(p, J ═ 5.9Hz, 2H), ESI-MS M/z calculated 239.0349, experimental 240.0(M +1)⁺(ii) a Retention time: 3.95min (LC method Q).

And step 3: (4S) -4- [3- [ [6- [ [ 2-chloro-6- (3, 4-dihydro-2H-pyran-6-yl) pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of 2-chloro-6- (3, 4-dihydro-2H-pyran-6-yl) pyridine-3-carboxylic acid (349mg, 1.456mmol) in THF (8.0mL) was added carbonyldiimidazole (252mg, 1.554mmol) and the mixture was stirred at room temperature for 20 hours. Then, (4S) -2, 2-dimethyl-4- [3- [ (6-sulfamoyl-2-pyridyl) -amino group is added]Propyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (400mg, 0.9696mmol) was followed by addition of DBU (475. mu.L, 3.176 mmol) and the resulting mixture was stirred at room temperature for 3 hours. The reaction was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was further washed with 10% aqueous citric acid, followed by brine the organics were separated, dried over sodium sulfate, filtered, evaporated and then purified by silica gel chromatography using a gradient of 100% hexane to 100% ethyl acetate by preparative reverse phase HPLC (C)₁₈Column, 30% -99% acetonitrile/water + hydrochloric acid modifier) to obtain (4S) -4- [3- [ [6- [ [ 2-chloro-6- (3, 4-dihydro-2H-pyran-6-yl) pyridine-3-carbonyl) as a white solid ]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (140mg, 23%). ESI-MS calculated M/z 633.2388, Experimental 634.2(M +1)⁺(ii) a Retention time: 2.11min (LC method B).

And 4, step 4: 2-chloro-6- (3, 4-dihydro-2H-pyran-6-yl) -N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] propylamino ] -2-pyridyl ] sulfonyl ] pyridine-3-carboxamide (trifluoroacetate)

Reacting (4S)4- [3- [ [6- [ [ 2-chloro-6- (3, 4-dihydro-2H-pyran-6-yl) pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]Propyl radical]Tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (140mg, 0.2208mmol) was dissolved in dichloromethane (610.8 μ L) and trifluoroacetic acid (681.1 μ L, 8.841mmol) was added to the mixture and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness under reduced pressure, 1mL of toluene was added, and removed by rotary evaporation (45 ℃ water bath). 1mL of toluene was again added and removed by rotary evaporation (45 ℃ water bath) followed by vacuum drying to give 2-chloro-6- (3, 4-dihydro-2H-pyran-6-yl) -N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl ] as a white solid]Propylamino group]-2-pyridyl]Sulfonyl radical]Pyridine-3-carboxamide (trifluoroacetate) (162.3mg, 100%). ESI-MS M/z calculated 533.18634, Experimental 534.3(M +1) ⁺(ii) a Retention time: 0.52min (LC method A).

And 5: (14S) -8- (3, 4-dihydro-2H-pyran-6-yl) -12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (compound 303)

To 2-chloro-6- (3, 4-dihydro-2H-pyran-6-yl) -N- [ [6- [3- [ (3S) -5, 5-dimethylpyrrolidin-3-yl)]Propylamino group]-2-pyridyl]Sulfonyl radical]Pyridine-3-carboxamide (trifluoroacetate) (162.3mg, 0.2204mmol) in NMP (8.591mL) potassium carbonate (213.8mg, 1.547mmol) was added, the mixture was purged with nitrogen for 5min, then heated to 180 ℃ and stirred overnight, cooled to room temperature, diluted with EtOAc, washed with 1N HCl, dried (sodium sulfate), filtered and concentrated to a brown oil which was filtered and purified by reverse phase HPLC (C.sub.L.) (C.sub.H.; HPLC)₁₈Column, 1% -99% acetonitrile/water (5mM HCl)) to give (14S) -8- (3, 4-dihydro-2H-pyran-6-yl) -12, 12-di-S-an as white solidMethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (3.31mg, 3%). ¹H NMR (400MHz, dimethylsulfoxide-d)₆)12.50(s, 1H), 7.66(d, J ═ 7.9Hz, 1H), 7.57(t, J ═ 7.9Hz, 1H), 7.04(d, J ═ 7.1Hz, 1H), 6.98(s, 1H), 6.76(d, J ═ 8.0Hz, 1H), 6.70(d, J ═ 8.5Hz, 1H), 5.94(s, 1H), 4.11(s, 2H), 3.92(d, J ═ 11.8Hz, 1H), 3.11(s, 1H), 2.93(d, J ═ 13.1Hz, 1H), 2.66(s, 1H), 2.20(d, J ═ 5.3Hz, 2H), 2.09(s, 1H), 1.83(d, J ═ 9, 3.3H), 1H (s, 1H), 1H, 3.49 (d, 1H), 1H, 3.49 (s, 1H), 1H, and 1H. ESI-MS M/z calculated 497.2097, Experimental 498.1(M +1)⁺(ii) a Retention time: 1.98min (LC method B).

Example 199: preparation of 8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-16, 16-difluoro-12, 12-dimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 1) (compound 305, SFC peak 1) and 8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-16, 16-difluoro-12, 12-dimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 2) (compound 304, SFC peak 2)

Step 1: 1- [ (4-methoxyphenyl) methyl ] -5, 5-dimethyl-pyrrolidin-2-one

The reaction was carried out in two batches.

Batch 1: a solution of 5, 5-dimethylpyrrolidin-2-one (121g, 1.0693mol) in DMF (1.8L) was cooled to 3 ℃ in an ice-water bath, followed by the addition of 60% nah in mineral oil (64.150 g, 1.6039mol) portion by portion over the course of approximately thirty minutes the mixture was stirred in an ice-water bath for a further thirty minutes, followed by stirring at room temperature for 1.5 hours. The resulting off-white slurry was again cooled to 3 ℃ in an ice-water bath, followed by the addition of 1- (chloromethyl) -4-methoxy-benzene (251.19g, 1.6039 mol). The ice water bath was removed after addition and the mixture was stirred overnight the reaction mixture was carefully quenched with water (100mL) and stored in the refrigerator overnight. The mixture was combined with the second batch prior to processing and purification.

Batch 2: a solution of 5, 5-dimethylpyrrolidin-2-one (484g, 4.2772mol) in DMF (7.2L) was cooled to 3 ℃ in a 20L jacketed reactor, followed by the addition of 60% NaH in mineral oil (256.61 g, 6.4158mol) in portions over a period of four hours. The resulting mixture was stirred at 3 ℃ for an additional hour, then at room temperature for two hours the resulting slurry was cooled again to 3 ℃ and then 1- (chloromethyl) -4-methoxy-benzene (1.0048kg, 6.4158mol) was added. The cooling system was stopped after the addition was complete and the resulting slurry was stirred overnight while being allowed to warm to room temperature. It was diluted with saturated ammonium chloride (10L), followed by extraction with ethyl acetate (4X 2L), the aqueous phase was discarded, and the combined organic phases were diluted with hexane (2L) and extracted with saturated ammonium chloride (2X 2L), followed by extraction with water (2L), the aqueous phase was discarded, and the organic phase was dried over sodium sulfate, the combined organic phases from the two treatments were concentrated in vacuo to give crude 1- [ (4-methoxyphenyl) methyl as a brown oil ]-5, 5-dimethyl-pyrrolidin-2-one (1.5 kg.) one kg of the crude product was purified by silica gel chromatography (0-100% ethyl acetate: hexane) to obtain pure 1- [ (4-methoxyphenyl) methyl ] as a yellow oil]5, 5-dimethyl-pyrrolidin-2-one (608g, 58%). ESI-MS m/zCalculations 233.1416, Experimental values 234.3(M +1)⁺(ii) a Retention time: 3.97min (LC method Q).

Step 2: 3-diethoxyphosphoryl-1- [ (4-methoxyphenyl) methyl ] -5, 5-dimethyl-pyrrolidin-2-one

A solution of diisopropylamine (529.14g, 732.88mL, 5.2292mol) in tetrahydrofuran (3.5L) was cooled to-75 ℃ in a dry ice-acetone bath, followed by the addition of n-butyllithium (2.092L, 2.5M, 5.2292mol) in a slow stream. The temperature was kept below-70 ℃ during the addition process the resulting yellow solution was stirred for thirty minutes followed by the addition of 1- [ (4-methoxyphenyl) methyl group in a slow stream]A solution of-5, 5-dimethyl-pyrrolidin-2-one (488g, 2.0917 mol) in tetrahydrofuran (1.5L) was stirred for an additional hour, the temperature was not allowed to exceed-70 ℃ during the addition. 1- [ chloro (ethoxy) phosphoryl]Oxyethane (541.38g, 451.15mL, 3.1376mol) was added dropwise to the reaction mixture, ensuring that the temperature remained below-70 ℃ during the course of the addition the resulting mixture was stirred for sixteen hours while it was allowed to thaw to room temperature the reaction was then quenched with 1M hydrochloric acid (3L) and extracted with ethyl acetate (2 x 2.4L). The aqueous phase was discarded and the combined organic phases were extracted with water (3X 2.4L.) the aqueous phase was discarded and the organic phase was dried over sodium sulfate and purified by silica gel chromatography (0-100% ethyl acetate/hexane) and then concentrated in vacuo to give 3-diethoxyphosphoryl-1- [ (4-methoxyphenyl) methyl ]-5, 5-dimethyl-pyrrolidin-2-one (677g, 81%). ESI-MS M/z calculated 369.1705, Experimental 370.1 (M +1)⁺(ii) a Retention time: 4.2min (LC method Q).

And step 3: n- (benzotriazol-1-ylmethyl) -N-benzyl-1-phenyl-methylamine

To a solution of benzotriazol-1-yl methanol (30g, 201.14mmol) in EtOH (600mL) at room temperatureTo this solution was added N-benzyl-1-phenyl-methylamine (39.680g, 38.674mL, 201.14mmol). before concentration in vacuo, the solution was stirred at room temperature for 1 hour, the residue was washed with diethyl ether (3 × 400mL) to give N- (benzotriazol-1-ylmethyl) -N-benzyl-1-phenyl-methylamine as a white solid (59.83g, 91%).¹H NMR (250MHz，CDCl₃)7.67-7.23(m，14H)，5.47(s，2H)，3.79(s，4H).

And 4, step 4: 3- (Benzylmethylamino) -2, 2-difluoro-propionic acid ethyl ester

To a suspension of Zn (17.3g, 2.4253mL, 264.57mmol) in THF (175mL) was added TMS-Cl (28.691g, 33.4mL, 264.09mmol) at room temperature, followed by ethyl 2-bromo-2, 2-difluoro-acetate (11.850g, 7.5mL, 58.380 mmol). The solution was stirred for 15min before N- (benzotriazol-1-ylmethyl) -N-benzyl-1-phenyl-methylamine (17.344g, 52.812mmol) in THF (100mL) was added dropwise to the reaction. The combined solution was stirred for 2 hours, then quenched with sodium bicarbonate (350mL) and extracted with ethyl acetate (3 × 500 mL). The combined organic layers were washed with water (750mL) and dried over sodium sulfate before being concentrated in vacuo. The organic residue was purified by silica gel chromatography, eluting with 0-15% diethyl ether/hexanes to give ethyl 3- (benzhydrylamino) -2, 2-difluoro-propionate (8.98g, 49%) as a clear liquid. ¹H NMR(500MHz，DMSO-d₆)7.37-7.29(m, 4H), 7.29-7.22(m, 6H), 4.13(q, J ═ 7.1Hz, 2H), 3.61(s, 4H), 3.15(t, J ═ 13.5Hz, 2H), 1.13(t, J ═ 7.1Hz, 3H). ESI-MS M/z calculated 333.154, Experimental 334.5(M +1)⁺(ii) a Retention time: 3.18min (LC method P).

And 5: 3- (benzhydrylamino) -2, 2-difluoro-propionaldehyde

To 3- (benzhydrylamino) -2, 2-difluoro-propionic acid ethyl ester at-78 deg.C(9.01g, 27.027mmol) to a solution in anhydrous DCM (125mL) was added diisobutylaluminum hydride (37.8mL, 1M, 37.800 mmol) dropwise, the reaction was stirred for 40min before quenching with citric acid (100mL) at-78 ℃. The solution was extracted with diethyl ether (3X 200mL), washed with brine (200mL) and dried over sodium sulfate, then concentrated in vacuo to give 3- (benzhydrylamino) -2, 2-difluoro-propionaldehyde (9.54g, 93%). ESI-MS M/z calculated 289.1278, experimental value 290.2(M +1)⁺(ii) a Retention time: 2.39 min (LC method P).

Step 6: 3- [3- (benzhydrylamino) -2, 2-difluoro-propylidene ] -1- [ (4-methoxyphenyl) methyl ] -5, 5-dimethyl-pyrrolidin-2-one

To 3-diethoxyphosphoryl-1- [ (4-methoxyphenyl) methyl group at 0 deg.C]To a solution of-5, 5-dimethyl-pyrrolidin-2-one (11.3g, 33.105mmol) in ACN (145mL) was added DIEA (5.1g, 6.8733mL, 39.461mmol) and LiCl (1.7g, 40.100 mmol). The solution was stirred at this temperature for 30min, after which 3- (benzhydrylamino) -2, 2-difluoro-propionaldehyde (9.544g, 32.988mmol) in ACN (50mL) was added at 0 ℃. The solution was quenched with a saturated solution of ammonium chloride (150mL) and then extracted with diethyl ether (3 x 200mL) and washed with brine (300mL), before being dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography, eluting with 0-25% ethyl acetate/hexanes to give 3- [3- (benzhydrylamino) -2, 2-difluoro-propylene ]-1- [ (4-methoxyphenyl) methyl group]-5, 5-dimethyl-pyrrolidin-2-one (E/Z isomer mixture) (8.03g, 48%).¹H NMR(250MHz，CDCl₃)7.36-7.22 (M, 10H), 7.21-7.15(M, 2H), 6.89-6.72(M, 2H), 6.67-5.75(M, 1H), 4.54-4.16(M, 2H), 3.85-3.60(M, 7H), 3.60-3.45(M, 1H), 3.19-2.79(M, 1H), 2.57-2.33(M, 2H), 1.22-0.98(M, 6H), ESI-MS M/z calculated 504.2588, Experimental 505.2(M +1)⁺(ii) a Retention time: 3.02min, 3.51min (LC method P).

And 7: 3- [3- (benzhydrylamino) -2, 2-difluoro-propyl ] -1- [ (4-methoxyphenyl) methyl ] -5, 5-dimethyl-pyrrolidin-2-one

To 3- [3- (benzhydrylamino) -2, 2-difluoro-propylene]-1- [ (4-methoxyphenyl) methyl group]To a solution of-5, 5-dimethyl-pyrrolidin-2-one (8g, 15.854mmol) in ethanol (400mL) was added Raney nickel (8g, 136.30 mmol). The resulting solution was hydrogenated in a barter shaker at 65PSI for 24 hours, then filtered through celite and washed with ethanol to provide the crude product. By flash chromatography (loaded on CH)₂Cl₂Middle) (220g SiO₂Eluting with 0 to 20% acetone/hexanes) to afford 3- [3- (benzhydrylamino) -2, 2-difluoro-propyl) as a pale yellow liquid ]-1- [ (4-methoxyphenyl) methyl group]-5, 5-dimethyl-pyrrolidin-2-one (4.97g, 56%).¹H NMR(250MHz，CDCl₃)7.43-7.29(m, 10H), 7.22(d J ═ 8.6Hz, 2H), 6.84(d, J ═ 8.6Hz, 2H), 4.38(s, 2H), 3.81(s, 3H), 3.78-3.50(m, 6H), 2.97-2.74 (m, 3H), 2.61-2.44(m, 1H), 2.21-2.01(m, 1H), 1.16(s, 3H), 0.93(s, 3H). ESI-MS M/z calculated 506.2745, Experimental 507.2(M +1)⁺(ii) a Retention time: 5.75min (LC method Q).

And 8: 3- [3- (benzhydrylamino) -2, 2-difluoro-propyl ] -5, 5-dimethyl-pyrrolidin-2-one

3- [3- (benzhydrylamino) -2, 2-difluoro-propyl ] into a container]-1- [ (4-methoxyphenyl) methyl group]-5, 5-dimethyl-pyrrolidin-2-one (4.97g, 8.9271mmol) to add TFA (100mL) followed by sealing the vessel and heating at 100 ℃ for 11 days all solvents were removed under reduced pressure the residue was dissolved in dichloromethane (300mL), washed with saturated aqueous sodium bicarbonate solution (3 x 100mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure flash chromatography(Loading in CH₂Cl₂Middle) (120g SiO₂Eluting with 0 to 45% ethyl acetate/hexanes) to afford 3- [3- (benzhydrylamino) -2, 2-difluoro-propyl) as a pale yellow liquid ]5, 5-dimethyl-pyrrolidin-2-one (2.28g, 66%). ESI-MS M/z calculated 386.217, experimental 387.3(M +1)⁺(ii) a Retention time: 3.29min (LC method Q).

And step 9: n, N-benzhydryl-3- (5, 5-dimethylpyrrolidin-3-yl) -2, 2-difluoro-propan-1-amine

To 3- [3- (benzhydrylamino) -2, 2-difluoro-propyl at 0 ℃ under nitrogen]To a stirred solution of-5, 5-dimethyl-pyrrolidin-2-one (2.23g, 5.7701mmol) in dry THF (100mL) was slowly added BH₃Me₂A solution of S (40mL, 2M, 80.000mmol) in THF. After the addition was complete, the reaction mixture was heated to 65 ℃ for 24 hours. The reaction mixture was cooled to 0 ℃ and slowly quenched with 6M aqueous HCl (50 mL.) methanol (50mL) was added and the reaction mixture was heated to 65 ℃ for 1 hour, cooled to room temperature, then NaHCO₃The reaction mixture was basified with a saturated aqueous solution (300mL) and the volatiles were removed under vacuum. The product was extracted with ethyl acetate (3X 150 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate and concentrated to give N, N-benzhydryl-3- (5, 5-dimethylpyrrolidin-3-yl) -2, 2-difluoro-propan-1-amine (2.46g, quantitative) as a yellow oil. ESI-MS M/z calculated 372.2377, Experimental 373.4(M +1) ⁺(ii) a Retention time: 3.87min (LC method Q).

Step 10: 4- [3- (benzhydrylamino) -2, 2-difluoro-propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred solution of N, N-benzhydryl-3- (5, 5-dimethylpyrrolidin-3-yl) -2, 2-difluoro-propan-1-amine (2.46g, 5.9437mmol) in DCM (80mL) was added triethylamine (1.0164g, 1.4mL, 10.044mmol) followed by Boc at 0 deg.C₂O (1.96g, 8.9807 mmol.) the reaction mixture was stirred at this temperature for 1 hour, the reaction was quenched with brine (100mL) and then warmed to room temperature, the two layers were separated and the aqueous layer was extracted with DCM (2 × 50mL), the combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was purified by silica gel chromatography using a gradient of 0-15% ethyl acetate/hexanes to give 4- [3- (benzhydrylamino) -2, 2-difluoro-propyl ] as a colorless oil]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.79 g, 94%). ESI-MS M/z calculated 472.2901, Experimental 473.5(M +1)⁺(ii) a Retention time: 7.45min (LC method Q).

Step 11: 4- (3-amino-2, 2-difluoro-propyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To 4- [3- (benzhydrylamino) -2, 2-difluoro-propyl at room temperature under nitrogen ]To a stirred solution of tert-butyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (2.68g, 5.6706mmol) in dry methanol (60mL) was added palladium on carbon (2.1g, 10% w/w, 1.9733mmol) followed by ammonium formate (3.6g, 57.092 mmol). The reaction mixture was heated to 65 ℃ for 6 hours, cooled to room temperature, and then filtered through a pad of celite, the filter cake was washed with methanol (2 × 30mL), and the combined filtrates were concentrated in vacuo, the crude material was purified by silica gel chromatography using a gradient of 0-10% methanol in dichloromethane to give tert-butyl 4- (3-amino-2, 2-difluoro-propyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (1.34g, 77%) as a yellow oil.¹H NMR(250 MHz，CDCl₃)3.87-3.66(m, 1H), 3.32(s, 3H), 3.13-2.86(m, 3H), 2.52-2.32(m, 1H), 2.08-1.79(m, 3H), 1.57-1.24(m, 15H). ESI-MS M/z calculated 292.1962, Experimental 293.5(M +1)⁺(ii) a Retention time: 3.55min (LC method Q).

Step 12: 4- [2, 2-difluoro-3- [ (6-sulfamoyl-2-pyridyl) -amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred solution of tert-butyl 4- (3-amino-2, 2-difluoro-propyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (1.24g, 4.2413mmol) and 6-fluoropyridine-2-sulfonamide (1.12g, 6.3934mmol) in anhydrous DMSO (7mL) at room temperature under nitrogen was added DIEA (1.7020g, 2.3mL, 13.169 mmol). The reaction mixture was heated to 120 ℃ for 30 hours. After cooling to room temperature, the reaction mixture was diluted with water (50mL) and brine (150mL) and the product was extracted with ethyl acetate (3X 100 mL). The combined organic layers were washed with brine (50mL), dried over anhydrous sodium sulfate and concentrated by reverse phase HPLC using a water-acetonitrile gradient (C) ₁₈Varian column, 50-90% acetonitrile, 60mL/min) to give 4- [2, 2-difluoro-3- [ (6-sulfamoyl-2-pyridyl) amino as a white foam]Propyl radical]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (574mg, 29%).¹H NMR(500MHz，DMSO-d₆)7.58(dd, J ═ 8.4, 7.2Hz, 1H), 7.37(t, J ═ 6.4 Hz, 1H), 7.16(s, 2H), 7.06-7.00(M, 1H), 6.75(d, J ═ 8.7Hz, 1H), 3.96-3.81(M, 2H), 3.64-3.51(M, 1H), 2.83(q, J ═ 10.4Hz, 1H), 2.42-2.29(M, 1H), 2.10-1.82 (M, 3H), 1.54-1.42(M, 1H), 1.41-1.30(M, 12H), 1.23(s, 3H), ESI-calculated value-MS M/z 448.1956, experimental value 449.2(M +1)⁺(ii) a Retention time: 2.38min (LC method P).

Step 13: 4- [3- [ [6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1] hept-7-ylethoxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] -2, 2-difluoro-propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

Round a 100mL circle under nitrogen2-chloro-6- [3- (2-dispiro [2.0.2.1]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (457mg, 1.270mmol) and anhydrous THF (8 mL). CDI (355 mg, 2.189mmol) was added and the mixture was stirred at room temperature under nitrogen for 15 h. Preparation of 4- [2, 2-difluoro-3- [ (6-sulfamoyl-2-pyridyl) amino group in a separate 20mL flask under a nitrogen atmosphere ]Propyl radical]-a solution of tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (570mg, 1.271mmol) in anhydrous THF (4mL) and subsequently added to the activated ester solution by syringe. DBU (0.78mL, 5.216mmol) was added by syringe and the reaction mixture was stirred at room temperature under nitrogen atmosphere for 5 h the solvent was removed under reduced pressure and the resulting thick oil was treated with ethyl acetate (35mL) and water (35mL), HCl (1.5 mL, 6M, 9.000mmol) was added slowly (final pH 5) and the phases were separated. The aqueous phase was extracted with EtOAc (30 mL). The combined extracts were washed with brine (30mL) and dried over sodium sulfate. After evaporation of the solvent, the residue was dissolved in DCM and purified by flash chromatography on silica gel (80g gold column) using a gradient of ethyl acetate/hexane (0 to 100% over 30 min.) the product was eluted at 45-65% EtOAc the pure fractions were combined and the solvent was evaporated to give 4- [3- [ [6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1 ] as a colourless resin]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]-2, 2-difluoro-propyl]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (667mg, 66%). ESI-MS calculated M/z 789.2887, Experimental 790.54(M +1) ⁺(ii) a Retention time: 2.51min (LC method B).

Step 14: 2-chloro-N- [ [6- [ [3- (5, 5-dimethylpyrrolidin-3-yl) -2, 2-difluoro-propyl ] amino ] -2-pyridinyl ] sulfonyl ] -6- [3- (2-dispiro [2.0.2.1] hept-7-ylethoxy) pyrazol-1-yl ] pyridine-3-carboxamide (dihydrochloride)

100mL was charged with 4- [3- [ [6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]-2, 2-difluoro-propyl]-2, 2-dimethyl-pyrroleAlkane-1-carboxylic acid tert-butyl ester (667mg, 0.8440mmol), DCM (8mL) and HCl (1.25mL, 4M in dioxane, 5.000 mmol). The reaction was stirred at room temperature for 1.5 hours the volatiles were removed by evaporation in vacuo. The residue was triturated with DCM/hexane and the solvent was evaporated. This operation was repeated until a good white solid was obtained. Vacuum drying to obtain 2-chloro-N- [ [6- [ [3- (5, 5-dimethylpyrrolidin-3-yl) -2, 2-difluoro-propyl ] as white solid]Amino group]-2-pyridyl]Sulfonyl radical]-6- [3- (2-dispiro [2.0.2.1]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carboxamide (dihydrochloride) (570mg, 89%). ESI-MS M/z calculated 689.23627, Experimental 690.3(M +1)⁺(ii) a Retention time: 1.77min (LC method B).

Step 15: 8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-16, 16-difluoro-12, 12-dimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 1) (compound 305, SFC peak 1) and 8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-16, 16-difluoro-12, 12-dimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 2) (compound 304, SFC peak 2)

A100 mL round bottom flask equipped with a magnetic stir bar was charged under nitrogen with 2-chloro-N- [ [6- [ [3- (5, 5-dimethylpyrrolidin-3-yl) -2, 2-difluoro-propyl]Amino group]-2-pyridyl]Sulfonyl radical]-6- [3- (2-dispiro [2.0.2.1 ]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carboxamide (dihydrochloride) (570mg, 0.7469mmol), anhydrous NMP (24mL) and K₂CO₃(766mg, 5.542mmol) (325 mesh.) the mixture was stirred vigorously in a dry bath at 150 ℃ for 18 hours under nitrogen. After cooling to room temperature, the mixture was poured into cooling water (200mL) and acidified (gentle foaming) by addition of HCl (2mL, 6M, 12.00 mmol). In Buchner The resulting solid was filtered on the funnel and air dried approximately the solid was dissolved in DCM and a small amount of methanol and the resulting cloudy solution was evaporated. The product was purified by flash chromatography on silica gel (gold 40g column) using a gradient of methanol/dichloromethane (0 to 5% over 30 min.) the product eluted at about 1% methanol. Evaporation of the solvent followed by trituration in DCM/hexane and evaporation of the solvent gave rac-8- [3- (2- { dispiro [2.0.2.1 ] as an off-white solid]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-16, 16-difluoro-12, 12-dimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (404mg, 83%). ESI-MS M/z calculated 653.2596, Experimental 654.33(M +1)⁺(ii) a Retention time: 2.34min (LC method B).

Through chiral SFC (using ChiralPak AS-3 (250X 21.2mm), 5. mu.M column at 40 ℃, mobile phase 24% MeOH (without modifier), 76% CO₂Flow rate: 70mL/min, concentration: 31mg/mL in MeOH, injection volume: 500 μ L, pressure: 156 bar, wavelength: 280nm) the two enantiomers each of the enantiomers was purified a second time by flash chromatography on silica gel (24g column) using a gradient of methanol/dichloromethane (0 to 5% over 30min) after evaporation of the solvent, the compound was triturated in DCM/hexane after evaporation of the solvent to give the two enantiomers as white solids.

Compound 305, SFC peak 1.ee > 98%. 8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-16, 16-difluoro-12, 12-dimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 1) (174mg, 70%).¹H NMR(500MHz，DMSO-d₆)12.54(s, 1H), 8.22(d, J ═ 2.8 Hz, 1H), 7.87(d, J ═ 8.2Hz, 1H), 7.71(t, J ═ 7.9Hz, 1H), 7.52(d, J ═ 10.2Hz, 1H), 7.22(d, J ═ 7.2Hz, 1H), 6.96(d, J ═ 8.3Hz, 2H), 6.10(d, J ═ 2.7Hz, 1H), 4.48(dt, J ═ 37.1, 12.7Hz, 1H), 4.22(t, J ═ 6.8Hz, 2H), 3.30 (width s, 1H), 3.12(t, J ═ 8.6Hz, 1H), 2.77(t, J ═ 10.6, 1H), 2.39.39 (t, J ═ 2H), 1H, 7(t, 1H), and 7H)(br s, 1H), 2.27-2.03(m, 2H), 1.93(dd, J ═ 11.7, 5.2 Hz, 1H), 1.82(q, J ═ 6.6Hz, 2H), 1.72(t, J ═ 12.4Hz, 1H), 1.63(s, 3H), 1.54(s, 3H), 1.48(t, J ═ 6.6Hz, 1H), 0.90-0.75(m, 4H), 0.69-0.60(m, 2H), 0.55-0.39(m, 2H). ESI-MS M/z calculated 653.2596, Experimental 654.33(M +1)⁺(ii) a Retention time: 2.34min (LC method B).

Compound 304, SFC peak 2.ee > 98%. 8- [3- (2- { dispiro [2.0.2.1 ] ]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-16, 16-difluoro-12, 12-dimethyl-2 λ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 2) (178mg, 71%).¹H NMR(500MHz，DMSO-d₆)12.53(s, 1H), 8.22(d, J ═ 2.8 Hz, 1H), 7.87(d, J ═ 8.2Hz, 1H), 7.71(t, J ═ 7.9Hz, 1H), 7.52(d, J ═ 10.1Hz, 1H), 7.21(d, J ═ 7.2Hz, 1H), 6.96(d, J ═ 8.3Hz, 2H), 6.10(d, J ═ 2.7Hz, 1H), 4.48(dt, J ═ 37.3, 12.4Hz, 1H), 4.22(t, J ═ 6.7Hz, 2H), 3.30 (width s, 1H), 3.12(t, J ═ 8.6, 1H), 2.77(t, J ═ 10.6H, 2H), 3.30 (width s, 1H), 3.12(t, J ═ 8.6, 1H), 2.77(t, J ═ 10, 2H), 2.6H, 2.7H), 3.7H, 3.6H, 3.7H, 3, 1H) 0.90-0.77(m, 4H), 0.72-0.60(m, 2H), 0.56-0.45(m, 2H). ESI-MS M/z calculated 653.2596, Experimental 654.33(M +1)⁺(ii) a Retention time: 2.34min (LC method B).

Example 200: preparation of 8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-16-fluoro-12, 12-dimethyl-2 lambda ⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 1) (compound 309, SFC peak 1), 8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-16-fluoro-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 2) (compound308, SFC Peak 2), 8- [3- (2- { Dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-16-fluoro-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 3) (compound 307, SFC peak 3) and 8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-16-fluoro-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 4) (compound 306, SFC peak 4)

Step 1: 3-allyl-1- [ (4-methoxyphenyl) methyl ] -5, 5-dimethyl-pyrrolidin-2-one

A solution of diisopropylamine (4.3372g, 6.0mL, 42.862mmol) in tetrahydrofuran (100mL) was cooled to-78 deg.C and n-butyllithium (17.1mL, 2.5M, 42.862mmol) was added dropwise the solution stirred for thirty minutes followed by the dropwise addition of 1- [ (4-methoxyphenyl) methyl]-a solution of 5, 5-dimethyl-pyrrolidin-2-one (10 g, 42.862mmol) in THF (10mL) and then stirred for one hour. 3-Bromoprop-1-ene (5.1853g, 3.71mL, 42.862mmol) was added dropwise to the reaction mixture, stirred at-78 ℃ for one hour and then allowed to warm to 0 ℃ over 30 minutes, then the reaction was quenched with saturated ammonium chloride (100mL) and extracted with ethyl acetate (3X 50mL), the combined organic phases were dried over sodium sulfate and purified by silica gel chromatography (0-20% ethyl acetate/hexanes) to give 3-allyl-1- [ (4-methoxyphenyl) methyl ] methyl]-5, 5-dimethyl-pyrrolidin-2-one (8.75g, 71%). ESI-MS M/z calculated 273.1729, Experimental 274.0(M +1)⁺(ii) a Retention time: 2.97min (LC method P).

Step 2: 3-allyl-5, 5-dimethyl-pyrrolidin-2-one

3-allyl-1- [ (4-methoxyphenyl) methyl]-5, 5-dimethyl-pyrrolidin-2-one (7.75g, 28.350 mmol) was dissolved in acetonitrile (140mL) and water (16mL) followed by the addition of ceric ammonium nitrate (64.559 g, 113.40mmol) portionwise at room temperature and the reaction stirred for 3 h then it was quenched with brine (300mL) and extracted with EtOAc (3 × 150 mL). The organic fractions were combined, dried over sodium sulfate and evaporated, and the residue was purified by silica gel column chromatography using 0-100% hexane-ethyl acetate to give 3-allyl-5, 5-dimethyl-pyrrolidin-2-one (3.77g, 76%). ESI-MS M/z calculated 153.1154, experimental 154.2(M +1) ⁺(ii) a Retention time: 1.61min (LC method P).

And step 3: 4-allyl-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

A solution of 3-allyl-5, 5-dimethyl-pyrrolidin-2-one (3.77g, 24.605mmol) in THF (25mL) was added dropwise to LiAlH under reflux₄(2.8016g, 3.05mL, 73.815mmol) in THF (50 mL). The mixture was refluxed for 3 hours, cooled to 0 ℃, and then water (2.8mL) was added very slowly, followed by 15% w/w sodium hydroxide (2.8mL) and water (8.4mL)₂O (6.4440g, 6.7832mL, 29.526mmol). the mixture was stirred for 16h, filtered and the filter cake was triturated with THF the organic fractions were combined and evaporated, and the residue was purified by column chromatography on silica gel using 0-5% ethyl acetate/hexanes to give 4-allyl-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (5.06g, 77%).¹H NMR (250MHz, chloroform-d) 5.93-5.58(m, 1H), 5.15-4.89 (m, 2H), 3.82-3.48(m, 1H), 2.90(q, J ═ 10.9Hz, 1H), 2.32-1.97(m, 3H), 1.94-1.75(m, 1H), 1.50-1.25(m, 16H)Calculated MS M/z 239.1885, Experimental value 240.3(M +1)⁺(ii) a Retention time: 3.53min (LC method P).

And 4, step 4: 4- (3-bromo-2-fluoro-propyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

A solution of tert-butyl 4-allyl-2, 2-dimethyl-pyrrolidine-1-carboxylate (500mg, 1.8801mmol) and triethylamine trihydrofluoride (710mg, 1.6296mmol) in DCM (10mL) was cooled to 0 deg.C and NBS (500mg, 2.8092mmol) was added. The mixture was allowed to warm to room temperature and stirred for 4 h the mixture was quenched with saturated sodium bicarbonate (50mL), the aqueous phase was separated and extracted with DCM (100 mL). The organic fractions were combined, dried over sodium sulfate and evaporated the residue was purified by silica gel column chromatography using 0-10% ethyl acetate/hexanes to give tert-butyl 4- (3-bromo-2-fluoro-propyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (420mg, 65%) as a colorless oil.¹H NMR(250MHz，CDCl₃)4.87-4.42(M, 1H), 3.86-3.54(M, 1H), 3.55-3.22(M, 2H), 3.07-2.75(M, 1H), 2.56-2.18(M, 1H), 2.12-1.71(M, 3H), 1.71-1.57(M, 1H), 1.51-1.38(M, 12H), 1.35-1.24(M, 3H), ESI-MS M/z calculated value 337.1053, experimental value 338.5(M +1)⁺(ii) a Retention time: 3.59min (LC method P).

And 5: 4- (3-amino-2-fluoro-propyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of 4- (3-bromo-2-fluoro-propyl) -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.26g, 6.5477mmol) in DMF (28ml) was added NaN ₃(0.6g, 9.1832mmol), and the mixture was stirred at 45 ℃ for 18 h the mixture was diluted with water (150mL), then saturated sodium bicarbonate (150mL) and the mixture was extracted with ethyl acetate (2X 200mL), the organic layer was washed with brine (300mL), dried over sodium sulfate, filtered and concentratedTo a solution of this azide intermediate oil in ethyl acetate (30mL) was added platinum oxide monohydrate (0.5g, 2.2018 mmol). The mixture was hydrogenated in a Barl shaker at 40psi for 1 hour, the reaction mixture was filtered through a pad of celite, the filtrate was concentrated to give tert-butyl 4- (3-amino-2-fluoro-propyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (1.59g, 87%) as a dark oil, ESI-MS M/z calculated 274.2057, experimental 275.6(M +1)⁺(ii) a Retention time: 3.51min (LC method Q).

Step 6: 4- [ 2-fluoro-3- [ (6-sulfamoyl-2-pyridyl) -amino ] propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To a mixture of tert-butyl 4- (3-amino-2-fluoro-propyl) -2, 2-dimethyl-pyrrolidine-1-carboxylate (1.59g, 5.6791 mmol) and 6-fluoropyridine-2-sulfonamide (1.3g, 7.0103mmol) in DMSO (10mL) was added DIEA (2.2260g, 3mL, 17.223 mmol). The mixture was stirred at 110 ℃ for 16 hours. The mixture was cooled to room temperature and treated with water/brine (100/100mL) and ethyl acetate (150 mL). The organic layer was dried over sodium sulfate, filtered through a pad of celite and concentrated. The residue (2.1g, combined with 0.56g of product from the previous reaction) was dissolved in DMSO (10mL) and loaded on a preparative-HPLC column (Varian C) ₁₈10 μm 5X 30 cm; flow rate: 60 mL/min; mobile phase A: water; mobile phase B: acetonitrile; the method comprises the following steps: 40-90% B over 45 min). The pure fractions were combined and concentrated to remove acetonitrile the resulting aqueous phase was extracted with ethyl acetate (2X 100mL) the organic layer was washed with brine (200mL), dried over sodium sulfate and concentrated to give 4- [ 2-fluoro-3- [ (6-sulfamoyl-2-pyridyl) amino as a white solid]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.5g, 58%).¹H NMR(250MHz，DMSO-d₆)7.56(t，J＝ 7.8Hz，1H)，7.27(t，J＝5.8Hz，1H)，7.12(s，2H)，7.00(d，J＝7.1Hz，1H)，6.71(d，J ＝8.4Hz，1H)，4.95-4.46(m，1H)，3.77-3.40(m，3H)，2.95-2.73(M, 1H), 2.40-2.15 (M, 1H), 2.02-1.85(M, 1H), 1.83-1.57(M, 3H), 1.54-1.29(M, 12H), 1.25(s, 3H), ESI-MS M/z calculated 430.205, experimental 431.5(M +1)⁺(ii) a Retention time: 2.35min (LC method R).

And 7: 4- [3- [ [6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1] hept-7-ylethoxy) pyrazol-1-yl ] pyridine-3-carbonyl ] sulfamoyl ] -2-pyridinyl ] amino ] -2-fluoro-propyl ] -2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

A100 mL round bottom flask was charged with 2-chloro-6- [3- (2-dispiro [2.0.2.1] under nitrogen]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carboxylic acid (573mg, 1.593mmol) and anhydrous THF (10 mL.) CDI (315 mg, 1.943mmol) was added and the mixture was stirred at room temperature under nitrogen for 2 hours. An additional 150mg of CDI was added and the mixture was stirred at room temperature for 15 hours to reach complete conversion in a separate 20mL flask, 4- [ 2-fluoro-3- [ (6-sulfamoyl-2-pyridyl) amino was prepared under a nitrogen atmosphere ]Propyl radical]-2, 2-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (693mg, 1.610mmol) in anhydrous THF (5mL) and subsequently added to the activated ester solution by syringe DBU (0.96mL, 6.419mmol) was added by syringe and the reaction mixture was stirred at room temperature under nitrogen atmosphere for 5 h. The solvent was removed under reduced pressure and the resulting thick oil was treated with ethyl acetate (40mL) and water (40mL) HCl (1.8mL, 6M, 10.80 mmol) was added slowly (final pH 5) and the two phases were separated. After evaporation of the solvent, the residue (1.34g) was dissolved in DCM and purified by flash chromatography on silica gel (80g gold column) using a gradient of ethyl acetate/hexane (0 to 100% over 30 min). The product was eluted at 45-65% EtOAc. The pure fractions were combined and the solvent was evaporated to give 4- [3- [ [6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1 ]) as a white foamy solid]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]-2-fluoro-propyl]-2, 2-dimethyl-pyrrolidine-1-tert-butyl formate (804mg, 65%). ESI-MS M/z calculated 771.2981, Experimental 772.39(M +1) ⁺(ii) a Retention time: the 2 diastereomers are found, 1: 1, Rt 2.51 and Rt 2.52min (LC method B). The product was used in the next step without any further purification.

And 8: 2-chloro-N- [ [6- [ [3- (5, 5-dimethylpyrrolidin-3-yl) -2-fluoro-propyl ] amino ] -2-pyridinyl ] sulfonyl ] -6- [3- (2-dispiro [2.0.2.1] hept-7-ylethoxy) pyrazol-1-yl ] pyridine-3-carboxamide (dihydrochloride)

A100 mL flask was charged with 4- [3- [ [6- [ [ 2-chloro-6- [3- (2-dispiro [2.0.2.1]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carbonyl]Sulfamoyl radical]-2-pyridyl]Amino group]-2-fluoro-propyl]-tert-butyl 2, 2-dimethyl-pyrrolidine-1-carboxylate (782mg, 1.013mmol), DCM (9mL) and HCl (1.5mL, 4M in dioxane, 6.000mmol) the reaction was stirred at room temperature for approximately 5 hours the volatiles were removed by vacuum evaporation the residue was triturated with DCM/hexane and the solvent was evaporated the operation was repeated until a good white solid was obtained 2-chloro-N- [ [6- [ [3- (5, 5-dimethylpyrrolidin-3-yl) -2-fluoro-propyl ] as a white solid]Amino group]-2-pyridyl]Sulfonyl radical]-6- [3- (2-dispiro [2.0.2.1]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carboxamide (dihydrochloride) (731mg, 97%). ESI-MS calculated M/z 671.24567, Experimental 672.44(M +1) ⁺(ii) a Retention time: 1.75min (LC method B).

And step 9: 8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-16-fluoro-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 1) (compound 309, SFC peak 1), 8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-16-fluoro-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111，14.05，10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 2) (compound 308, SFC peak 2), 8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-16-fluoro-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosan-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 3) (compound 307, SFC peak 3) and 8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-16-fluoro-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 4) (compound 306, SFC peak 4)

A100 mL round bottom flask equipped with a magnetic stir bar was charged under nitrogen with 2-chloro-N- [ [6- [ [3- (5, 5-dimethylpyrrolidin-3-yl) -2-fluoro-propyl ] -N]Amino group]-2-pyridyl]Sulfonyl radical]-6- [3- (2-dispiro [2.0.2.1 ]]Hept-7-ylethoxy) pyrazol-1-yl]Pyridine-3-carboxamide (dihydrochloride) (723mg, 0.9703mmol), Anhydrous NMP (30mL) and K₂CO₃(996mg, 7.207mmol) (325 mesh.) the mixture was stirred vigorously in a dry bath at 150 ℃ under nitrogen for 18 h after cooling to room temperature, the mixture was poured into cooling water (300mL) and acidified (gently foaming) by addition of HCl (2.5mL, 6M, 15.00mmol), the resulting solid was filtered on a Buchner funnel and air dried approximately, the solid was dissolved in DCM and a small amount of methanol and the resulting cloudy solution was dried over sodium sulfate after concentration (910mg of crude solid) the solution was purified by silica gel flash chromatography (gold 80g column) using a gradient of methanol/dichloromethane (0 to 5% over 30 min.) the product was eluted under about 2-3% methanol. Evaporation of the solvent followed by trituration in DCM/hexanes and evaporation of the solvent gave 8- [3- (2- { dispiro [2.0.2.1 ] as an off-white solid]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-16-fluoro-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (467mg, 76%) (mixture of 4 isomers).¹H NMR(500MHz，DMSO-d₆) Several diastereomers 12.57 and 12.50 (two s, together 1H), 8.25-8.19(m, 1H), 7.83(d, J ═ 8.2Hz, 1H), 7.65(q, J ═ 8.0Hz, 1H), 7.37-7.11 (m, 2H), 6.98-6.74(m, 2H), 6.10(dd, J ═ 4.6, 2.7Hz, 1H), 4.87(d, J ═ 43.7Hz, 1H), 4.32-4.04(m, 3H), 3.29-2.97(m, 2H), 2.92-2.60(m, 1H), 2.47-2.23(m, 1H), 2.18-1.76(m, 5H), 1.75-1.44(m, 8H), 0.56-0.56H, 56-0.56H), 0.56-0.56H, 56-2H, 1H) were observed. ESI-MS M/z calculated 635.269, Experimental 636.37(M +1)⁺(ii) a Retention time: two peaks are seen, Rt 2.32 and Rt 2.34min (LC method B).

The four stereoisomers are separated in two stages by chiral SFC. The sample was first purified using the normal phase SFC-MS method using a LUX-4 column (250X 21.2mm, 5 μm particle size) (pn: 00G-4491-P0-AX) sold by Phenomenex, mobile phase 41% MeOH (without modifier), 59% CO₂70 mL/min, 31mg/mL in MeOH, injected at 500 μ L column temperature 40 ℃, pressure 178 bar, wavelength 280nM. this separated peaks 1 and 2 with

peaks

3 and 4 eluting together after evaporation of the

solvent peaks

3 and 4 were separated using the following (216mg solid): chiralPak AS-3 column (250X 21.2mm), 5. mu.M, mobile phase 28% MeOH (no modifier), 72% CO ₂70mL/min, 31mg/mL in MeOH, 500. mu.L injection volume, pressure 156 bar, wavelength 280 mm. After evaporation of the solvent, each compound was purified by flash chromatography on silica gel (12g column) using a gradient of methanol/dichloromethane (0 to 5% over 15 min.) for each separated isomer, the solvent was evaporated and the residue was triturated in DCM/hexane. Evaporation of the solvent gave the product as an off-white solid, peak 1/2 and peak 3/4 formed enantiomeric pairs based on LC retention time. This was confirmed by mixing peak 2 with peak 3 QC solution (which produced two separate peaks). sub.4 isomers¹H NMR overlap confirmed the following observations:

peaks

1 and 2 have the same¹H NMR spectrum, and Peak 3¹The HNMR spectrum is consistent with peak 4.

Compound 309, SFC Peak 1.ee > 98%. 8- [3- (2- { dispiro [2 ].0.2.1]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-16-fluoro-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 1) (98mg, 61%).¹H NMR(500MHz，DMSO-d₆)12.50 (width s, 1H), 8.22(s, 1H), 7.82(br s, 1H), 7.66(t, J ═ 7.9Hz, 1H), 7.24(br s, 1H), 7.19-7.13(br m, 1H), 6.95 (d, J ═ 8.2Hz, 1H), 6.78(br s, 1H), 6.10(d, J ═ 2.9Hz, 1H), 4.83(br d, 1H), 4.22(br s, 2H), 4.12(br s, 1H), 3.26-3.02(br m, 2H), 2.82(br s, 1H), 2.44(br s, 1H), 2.08(br s, 1H), 1.98-1.44(m, 12H), 0.89-0.75(m, 0.89H), 0.75-0.60H, 0.55H), 0.55-0.60H (br m, 0H). ESI-MS M/z calculated 635.269, Experimental 636.37(M +1) ⁺(ii) a Retention time: 2.33min (LC method B).

Compound 308, SFC peak 2. ee > 98%. 8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-16-fluoro-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 2) (98mg, 61%).¹H NMR(500MHz，DMSO-d₆)12.50(s, 1H), 8.23(d, J ═ 2.8Hz, 1H), 7.84(d, J ═ 7.4Hz, 1H), 7.66(t, J ═ 7.9Hz, 1H), 7.24 (width s, 1H), 7.17(d, J ═ 7.2 Hz, 1H), 6.96(d, J ═ 8.2Hz, 1H), 6.78(br s, 1H), 6.10(d, J ═ 2.7Hz, 1H), 4.83(br d, J ═ 44.5Hz, 1H), 4.23(tt, J ═ 6.8, 2.7Hz, 2H), 4.13(br s, 1H), 3.15(br s, 2H), 2.82 (br s, 1H), 2.44(br s, 2.7H), 2.42H, 1H, 0.7H), 2.7H, 3.7 (br s, 3.7H), 3.7 (br s, 1H), 3.15(br s, 2H), 2.82 (ESI, 1H), 2.82 (br s, 1H), 2.44, 2H), 0.7H, 2.7H), 0.7H, 3.7H, 0.7M, 3.7M, 3..⁺(ii) a Retention time: 2.33min (LC method B).

Compound 307, SFC Peak 3.ee > 98%. 8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-16-fluoro-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10 ]Tetracos-1 (22), 5, 7, 9, 19(23), 20-hexaene2, 2, 4-trione (enantiomer 3) (90mg, 56%).¹H NMR(500MHz，DMSO-d₆)12.57(s, 1H), 8.21(d, J ═ 2.8Hz, 1H), 7.83(d, J ═ 8.2Hz, 1H), 7.64(t, J ═ 7.9Hz, 1H), 7.33 (width d, J ═ 9.8Hz, 1H), 7.14(d, J ═ 7.2Hz, 1H), 6.94(t, J ═ 9.2Hz, 2H), 6.09(d, J ═ 2.8Hz, 1H), 4.88(d, J ═ 42.8Hz, 1H), 4.30-4.09(m, 3H), 3.36(m, 1H) overlapped with water, 3.01(t, J ═ 8.9Hz, 1H), 2.64(t, J ═ 10.7, 1H), 2.31 (s, 1H), 0.5 (m, 5-0.5H), 5(m, 5-0.8H, 1H, 5(m, 5H, 1H, 5H), experimental value 636.37(M +1)⁺(ii) a Retention time: 2.3min (LC method B).

Compound 306, SFC Peak 4.ee > 98%. 8- [3- (2- { dispiro [2.0.2.1 ]]Hept-7-yl } ethoxy) -1H-pyrazol-1-yl]-16-fluoro-12, 12-dimethyl-2 lambda⁶-thia-3, 9, 11, 18, 23-pentaazatetracyclo [17.3.1.111, 14.05, 10]Tetracosane-1 (22), 5, 7, 9, 19(23), 20-hexaen-2, 2, 4-trione (enantiomer 4) (74mg, 46%).¹H NMR(500MHz，DMSO-d₆)12.57(s, 1H), 8.21(d, J ═ 2.8Hz, 1H), 7.83(d, J ═ 8.2Hz, 1H), 7.64(t, J ═ 7.9Hz, 1H), 7.33 (wide d, J ═ 9.7Hz, 1H), 7.13(d, J ═ 7.2Hz, 1H), 6.94(dd, J ═ 10.6, 8.4Hz, 2H), 6.10(d, J ═ 2.7Hz, 1H), 4.88(d, J ═ 43.5Hz, 1H), 4.28-4.08(m, 3H), 3.35-3.24(m, 1H overlapped with water), 3.04-2.92 (m, 1H), 2.63(t, J ═ 10.9, 1H), 2.35-3.52 (m, 1H), 0.59-6.7H, 5H, 1H, 6.67 (m, 5H), 3.7H, 5H, 7H, 3.7H, 5H, 1H, 3.7H, 3.6.7H, 3.7H, 3.6.6.6.7H, and 0.7H, 2H) in that respect ESI-MS M/z calculated 635.269, Experimental 636.33(M +1) ⁺(ii) a Retention time: 2.3min (LC method B).

Biological activity assay

Solution scheme

The basal medium (ADF + + +) consists of: advanced DMEM/Ham's F12, 2mM Glutamax, 10mM HEPES, 1 μ/ml penicillin/streptomycin.

Intestinal enteroid (enteroid) maintenance medium (IEMM) consists of: ADF + + +, 1x B27 supplement, 1 XN 2 supplement, 1.25mM N-acetylcysteine, 10mM nicotinamide, 50ng/mL hEGF, 10nM gastrin, 1. mu.g/mL hR-spondin-1, 100ng/mL hNoggin, TGF-b 1-type inhibitor A-83-01, 100. mu.g/mL Primocin, 10. mu. M P38 MAPK inhibitor SB 202190.

Bath 1 buffer consisted of: 1mM MgCl₂160mM NaCl, 4.5mM KCl, 10mM HEPES, 10mM glucose, 2mM CaCl₂.

The chloride-free buffer consisted of: 1mM magnesium gluconate, 2mM calcium gluconate, 4.5mM potassium gluconate, 160mM sodium gluconate, 10mM HEPES, 10mM glucose.

Bath 1 dye solution consisted of: bath 1 buffer, 0.04% Pluronic F127, 20. mu.M methyloxanil (Methyl Oxonol), 30. mu.M CaCcih-A01, 30. mu.M Chicago sky blue.

The chlorine-free dye solution consisted of: chloride free buffer, 0.04% Pluronic F127, 20. mu.M methyl quinoxaline, 30. mu.M CaCcih-A01, 30. mu.M Chicago sky blue.

The chlorine-free dye-stimulating solution consisted of: chlorine-free dye solution, 10. mu.M forskolin, 100. mu.M IBMX and 300nM compound III.

Cell culture

Human intestinal epithelium-like intestinal cells were obtained from The Royal Institute of Developmental Biology and Stem Cell Research, The Netherlands, and expanded in T-flasks as previously described (Dekkers JF, Wiegerinck CL, de Jonge HR, Bronsveld I, Janssens HM, de Winter-de Groot KM, Brandsa AM, de Jong NWM, Bijvelds MJC, Scholte BJ, Nieuuphous husbandois EES, van den Brink, Clevelers H, van der Ent CK, Middendorp S, and M Beetnal JM 19. A functional bowel diagnosis CFtissue Research 937. 7. Nature 939. 7. incorporated).

Eintestinoid cell harvesting and seeding

Recovering the cells in a cell recovery solutionCells were harvested by centrifugation at 650rpm for 5min at 4 ℃, resuspended in TryPLE and incubated for 5min at 37 ℃ then harvested by centrifugation at 650rpm for 5min at 4 ℃ and resuspended in a medium containing 10. mu.M ROCK Inhibitor (RI) (trans-4- [ (1R) -1-aminoethyl ]N-4-pyridylcyclohexanecarboxamide) the cell suspension was flowed through a 40 μ M cell strainer and resuspended at 1 × 106 cells/ml in an IEMM containing 10 μ M RI. Prior to assay, cells were seeded into multi-well plates at 5000 cells/well and incubated at 37 deg.C, 95% humidity and 5% CO₂Incubate overnight.

Membrane potential dye assay

At 37 deg.C, 95% humidity and 5% CO in IEMM₂After compound incubation, the efficacy and efficacy of test compounds for CFTR-mediated chloride transport was measured directly using FLIPR Tetra, using a membrane potential dye assay, after acute addition of 10 μ M forskolin and 300nM compound III the efficacy and efficacy of test compounds for CFTR-mediated chloride transport briefly, cells were washed 5 times in bath 1 buffer, bath 1 dye solution was added, and cells were incubated at room temperature for 25min. Chlorine transport was then expressed as the percentage of chlorine transport (% activity) after three-fold control treatment with 3 μ M compound a, 3 μ M compound II, and 300nM acute compound III. Compound a is:

Table 5 reflects the results of the biological activity assays for exemplary compounds of the invention (maximum activity: +++ is > 60%; + is 30-60%; + is < 30%; EC 50: +++ is < 1. mu.M; + is 1-3. mu.M; + is > 3. mu.M; and ND is "undetermined").

Table 5:

other embodiments

One skilled in the art will readily recognize from such discussion, and from the accompanying drawings and claims, that various changes, modifications and variations can be made therein without departing from the spirit and scope of the disclosure as defined in the following claims.

Claims

1. A compound of formula I:

wherein:

-ring B is a pyridyl ring;

-X is O, NH or N (C1-C4 alkyl);

-m is 0, 1, 2, 3 or 4;

each R²Independently selected from C₁-C₂Alkyl radical, C₁-C₂Alkoxy radical, C ₁-C₂Haloalkyl, C₁-C₂Haloalkoxy, halogen, cyano and hydroxy;

-n is 0, 1 or 2;

each R³Is methyl;

-k is 0, 1, 2, 3, 4, 5 or 6;

each R⁵And R⁶Independently selected from hydrogen, halogen, hydroxy, C₁-C₄Alkyl and C_3-5Cycloalkyl radicals, or on the same carbonR of (A) to (B)⁵And R⁶Together form C_3-5Cycloalkyl or oxo;

-q is 1, 2, 3 or 4; and is

-Z is of formula (L)_rThe divalent linker of (1), wherein:

-r is 1, 2, 3, 4, 5 or 6;

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

2. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein the compound of formula (I) is a compound of formula (II-a) or (II-B):

wherein:

-the carbon represented by has S-stereochemistry or R-stereochemistry;

-ring B is a pyridyl ring;

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

-k is 0, 1, 2, 3, 4, 5 or 6;

each R⁵And R⁶Independent of each otherIs selected from hydrogen, halogen, hydroxy, C₁-C₄Alkyl and C_3-5Cycloalkyl radicals, or R on the same carbon⁵And R⁶Together form C_3-5Cycloalkyl or oxo;

-q is 1, 2, 3 or 4;

-Z is of formula (L)_rThe divalent linker of (1), wherein:

-r is 1, 2, 3, 4, 5 or 6;

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

3. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein the compound of formula I is a compound of formula (III-a) or (III-B):

wherein:

-the carbon represented by has S-stereochemistry or R-stereochemistry;

-ring B is a pyridyl ring;

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

-k is 0, 1, 2, 3, 4, 5 or 6;

-each Y is independently selected from C (R)⁵)(R⁶) The radicals, -O-and-NR^a-group in which- (Y)_k-R⁷Wherein the heteroatom is not bound to- (Y)_k-R⁷In anotherA heteroatom combination wherein:

-q is 1 or 2;

-Z is of formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

4. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein the compound of formula I is a compound of formula IV-a:

wherein:

-the carbon represented by has S-stereochemistry or R-stereochemistry;

x is O, NH or N (C)₁-C₄Alkyl groups);

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

-k is 0, 1, 2, 3, 4, 5 or 6;

-q is 1 or 2;

-Z is of formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

5. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein the compound of formula I is a compound of formula IV-B:

wherein:

-the carbon represented by has S-stereochemistry or R-stereochemistry;

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

each R⁴Independently selected from the group consisting of halogen, oxo, hydroxy, cyano and- (Y) _k-R⁷A group, or optionally, two R⁴Together with the atoms to which they are attached form a 5-to 6-membered cycloalkyl or heterocyclyl ring optionally and independently substituted with one or more groups selected from: halogen, C₁-C₂Alkyl, haloalkyl, hydroxy, C₁-C₂Alkoxy and C₁-C₂Haloalkoxy, wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

-q is 1 or 2;

-r is 3 or 4;

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

6. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein the compound of formula I is a compound of formulae IV-C:

wherein:

-the carbon represented by has S-stereochemistry or R-stereochemistry;

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

-k is 0, 1, 2, 3, 4, 5 or 6;

-each Y is independently selected from C (R)⁵)(R⁶) The radicals, -O-and-NR^a-group in which- (Y) _k-R⁷Wherein the heteroatom is not bound to- (Y)_k-R⁷Wherein:

-q is 1 or 2;

-r is 3 or 4;

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

7. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein the compound of formula I is a compound of formula V-a:

wherein:

-the carbon represented by has S-stereochemistry or R-stereochemistry;

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

-k is 0, 1, 2, 3, 4, 5 or 6;

-q is 1 or 2;

-Z is of formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

8. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein the compound of formula I is a compound of formula V-B:

wherein:

-the carbon represented by has S-stereochemistry or R-stereochemistry;

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

-k is 0, 1, 2, 3, 4, 5 or 6;

-q is 1 or 2;

-r is 3, 4 or 5; and is

9. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein the compound of formula I is a compound of formula VI-a or VI-B:

wherein:

-the carbon represented by has S-stereochemistry or R-stereochemistry;

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

-k is 0, 1, 2, 3, 4, 5 or 6;

-q is 1 or 2;

-Z is a bivalent linker of formula (L) r, wherein:

-r is 3, 4 or 5;

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

10. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein the compound of formula I is a compound of formula VI-C or VI-D:

wherein:

-the carbon represented by has S-stereochemistry or R-stereochemistry;

x is O, NH or N (C)₁-C₄Alkyl groups);

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

-k is 0, 1, 2, 3, 4, 5 or 6;

-q is 1 or 2;

-r is 3 or 4; and is

11. The compound, pharmaceutically acceptable salt thereof, or deuterated derivative of any one of the foregoing of claims 1-3, wherein ring a is a phenyl ring, a pyridinyl ring, or a pyrazolyl ring, wherein ring a is optionally substituted with (R)¹)_mAnd (4) substitution.

12. The compound of any one of claims 1-11, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is¹Independently selected from deuterium, C₁-C₂Alkyl and hydroxy, and m is 0 or 1.

13. The compound of any one of claims 1-11, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein n is 0.

14. The compound, pharmaceutically acceptable salt thereof, or deuterated derivative of any one of the foregoing as recited in any one of claims 1-5 and 7-10 wherein ring D is substituted with (R)⁴)_qA substituted 5-membered heteroaryl ring.

15. The compound, pharmaceutically acceptable salt thereof, or deuterated derivative of any one of the foregoing according to claim 1, wherein ring D is a phenyl ring, a pyridinyl ring, a pyrazolyl ring, an imidazolidinone ring, a pyrrolidinone ring, or a pyridone ring, wherein ring D is substituted with (R)⁴)_qAnd (4) substitution.

16. The compound of claim 2, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring D is a pyrazolyl ring or a pyridone ring, wherein ring D is substituted with R⁴And (4) substitution.

17. The compound, pharmaceutically acceptable salt thereof, or deuterated derivative of any one of the foregoing claims 3-5 and 7-10, wherein ring D is a pyrazolyl ring wherein ring D is substituted with (R) ⁴)_qAnd (4) substitution.

18. The compound of any one of claims 1-5 and 7-10, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring D is

Wherein

Indicating the point of attachment of ring D to ring B.

19. The compound of claim 18, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein ring D is

Wherein

Indicating the point of attachment of ring D to ring B.

20. The compound of any one of claims 1-19, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁴Independently selected from oxo or- (Y)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

each R⁵And R⁶Independently selected from hydrogen, deuterium, halogen, hydroxy, C₁-C₄Alkyl and C_3-5Cycloalkyl radicals, or R on the same carbon⁵And R⁶Together form C₃-₅Cycloalkyl or oxo;

21. The compound of any one of claims 1-20, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁴Independently selected from oxo or- (Y)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

22. The compound of any one of claims 1-19, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is ⁴Independently selected from oxo or-O- (Y)_k-R⁷A group wherein:

-k is 0, 1, 2, 3, 4 or 5;

23. The compound of any one of claims 1-22, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is⁴Is independently selected from

Wherein

Indication R⁴The point of attachment to loop D.

24. The compound of any one of claims 1-23, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein k is 3, 4, 5, or 6.

25. The compound of any one of claims 1 to 24, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein q is 1.

26. The compound of any one of claims 1 to 25, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein Z is formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Independently selected from hydrogen and deuterium; and is

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

27. The compound of any one of claims 1 to 25, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein Z is formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Independently selected from hydrogen and deuterium; and is

Each R^bIndependently selected from hydrogen and methyl.

28. The compound of any one of claims 1 to 25, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein Z is formula (L) _rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Independently selected from hydrogen and deuterium; and is

Each R^bIs hydrogen.

29. The compound of any one of claims 1 to 25, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein Z is formula (L)_rThe divalent linker of (1), wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Is hydrogen; and is

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

30. The compound of any one of claims 1 to 29, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein each R is³Independently of CD₃。

31. The compound of claim 5 or claim 6, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Independently selected from hydrogen and deuterium; and is

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

32. The compound of claim 5 or claim 6, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Independently selected from hydrogen and deuterium; and is

Each R^bIndependently selected from hydrogen and methyl.

33. The compound of claim 5 or claim 6, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Independently selected from hydrogen and deuterium; and is

Each R^bIs hydrogen.

34. The compound of claim 5 or claim 6, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein:

-r is 3, 4 or 5;

each R⁸And R⁹Is hydrogen; and is

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

35. The compound of claim 8 or claim 10, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein:

-r is 3, 4 or 5; and is

Each R⁸And R⁹Independently selected from hydrogen and deuterium.

36. The compound of claim 8 or claim 10, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein:

-r is 3, 4 or 5; and is

Each R⁸And R⁹Is hydrogen.

37. The compound of claim 8 or claim 10, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein:

-r is 3, 4 or 5; and is

Each R⁸And R⁹Is deuterium.

38. The compound of claim 8 or claim 10, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, wherein:

-r is 3 or 4; and is

Each R⁸And R⁹Is hydrogen.

39. A compound selected from the compounds depicted in figure 1, deuterated derivatives thereof, or pharmaceutically acceptable salts of any of those compounds or deuterated derivatives.

40. A pharmaceutical composition comprising at least one compound selected from the compound of any one of claims 1-39, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any one of the foregoing, and optionally one or more of the following:

(a) compound II:

(b) compound III or compound III-d:

(c) a pharmaceutically acceptable carrier.

41. A method of treating cystic fibrosis comprising administering to a patient in need thereof a compound of any one of claims 1-39 or a pharmaceutical composition according to claim 40.

42. Use of at least one compound selected from the compound of any one of claims 1-39, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing, and optionally one or more of:

(a) Compound II:

(b) compound III or compound III-d:

a deuterated derivative thereof or a pharmaceutically acceptable salt of any of the foregoing;

it is used for the treatment of cystic fibrosis.

43. A compound of formula (X):

a deuterated derivative thereof or a salt of any of the foregoing,

wherein:

-Q^ais halogen;

-ring B is a pyridyl ring;

x is O, NH or N (C)₁-C₄Alkyl groups);

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

-Z is of formula (L)_rThe divalent linker of (1), wherein:

-r is 1, 2, 3, 4, 5 or 6;

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

44. A compound of formula (Y):

a salt thereof or a deuterated derivative of any of the foregoing,

wherein:

-Q^bis halogen;

-R¹⁰is hydrogen or a protecting group;

-ring B is a pyridyl ring;

x is O, NH or N (C)₁-C₄Alkyl groups);

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

each R⁴Independently selected from halogenOxo, hydroxy, cyano and- (Y)_k-R⁷A group, or optionally, two R⁴Together with the atoms to which they are attached form a 5-to 6-membered cycloalkyl or heterocyclyl ring optionally and independently substituted with one or more groups selected from: halogen, C₁-C₂Alkyl, haloalkyl, hydroxy, C₁-C₂Alkoxy and C₁-C₂A haloalkoxy group; wherein:

-k is 0, 1, 2, 3, 4, 5 or 6;

-each Y is independently selected from C (R) ⁵)(R⁶) The radicals, -O-and-NR^a-group in which- (Y)_k-R⁷Wherein the heteroatom is not bound to- (Y)_k-R⁷Wherein:

-q is 1, 2, 3 or 4; and is

-Z is of formula (L)_rThe divalent linker of (1), wherein:

-r is 1, 2, 3, 4, 5 or 6;

-each L is independently selected from C (R)⁸)(R⁹) The radicals, -O-and-NR^bA group in which the hetero atom in Z isNot bound to another heteroatom in Z, wherein:

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

45. A process for preparing a compound of formula (I):

a pharmaceutically acceptable salt thereof or a deuterated derivative of any of the foregoing, comprising

Reacting the NH group of ring C of the compound of formula (Y-I), a salt thereof or a deuterated derivative of any of the foregoing with Q of ring B^bGroup coupling:

wherein:

-Q^bis halogen;

-ring B is a pyridyl ring;

x is O, NH or N (C)₁-C₄Alkyl groups);

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

-k is 0, 1, 2, 3, 4, 5 or 6;

-each Y is independently selected from C (R)⁵)(R⁶) The radicals, -O-and-NR ^a-group in which- (Y)_k-R⁷Wherein the heteroatom is not bound to- (Y)_k-R⁷Wherein:

-R⁷Selected from hydrogen, halogen, cyano and C optionally substituted by one or more groups selected from₃-C₁₀Cycloalkyl groups: c₁-C₂Alkyl, aryl, heteroaryl, and heteroaryl,C₁-C₂Haloalkyl and halogen;

-q is 1, 2, 3 or 4; and is

-Z is of formula (L)_rThe divalent linker of (1), wherein:

-r is 1, 2, 3, 4, 5 or 6;

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group;

-to form a compound of formula (I), a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing.

46. The process of claim 45, wherein the coupling is carried out in the presence of a base.

47. A process for preparing a compound of formula (Y)

A method of a salt thereof or a deuterated derivative of any of the foregoing, comprising

Reacting a compound of formula (a), a salt thereof, or a deuterated derivative of any of the foregoing with a compound of formula (B), a salt thereof, or a deuterated derivative of any of the foregoing to form the compound of formula (Y), a salt thereof, or a deuterated derivative of any of the foregoing:

and

optionally deprotecting said N-protecting group of ring C of formula (Y), wherein

Q^bIs halogen;

r of formula (Y)¹⁰Is hydrogen or an N-protecting group;

r of formula (B)¹⁰Is an N-protecting group, and

ring A, ring B, ring D, X, R¹、m、R²、n、R³、R⁴、q、Z、R¹⁰And wherein the variables are as recited in claim 1.

48. The method of claim 47, wherein the reacting a compound of formula (A), a salt thereof, or a deuterated derivative of any of the foregoing with a compound of formula (B), a salt thereof, or a deuterated derivative of any of the foregoing is carried out in the presence of a base.

49. The method of claim 48, wherein the reacting a compound of formula (A), a salt thereof, or a deuterated derivative of any of the foregoing with a compound of formula (B), a salt thereof, or a deuterated derivative of any of the foregoing comprises reacting a compound of formula (A), a salt thereof, or a deuterated derivative of any of the foregoing with a coupling agent and then with a compound of formula (B), a salt thereof, or a deuterated derivative of any of the foregoing in the presence of a base.

50. A process for preparing a compound of formula (Y-2):

-Q^bis halogen;

-ring B is a pyridyl ring;

x is O, NH or N (C)₁-C₄Alkyl groups);

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

-k is 0, 1, 2, 3, 4, 5 or 6;

-q is 1, 2, 3 or 4;

-r is 1, 2, 3, 4 or 5;

-R¹⁰Is hydrogen or a protecting group;

-the method comprises reacting a compound of formula (a), a salt thereof, or a deuterated derivative of any of the foregoing with a compound of formula (B-2), a salt thereof, or a deuterated derivative of any of the foregoing to form the compound of formula (Y-2), a salt thereof, or a deuterated derivative of any of the foregoing:

51. the method of claim 50, wherein the reacting a compound of formula (A), a salt thereof, or a deuterated derivative of any of the foregoing with a compound of formula (B-2), a salt thereof, or a deuterated derivative of any of the foregoing is carried out in the presence of a base.

52. The method of claim 51, wherein the reacting a compound of formula (A), a salt thereof, or a deuterated derivative of any of the foregoing with a compound of formula (B-2), a salt thereof, or a deuterated derivative of any of the foregoing comprises reacting a compound of formula (A), a salt thereof, or a deuterated derivative of any of the foregoing with a coupling agent and then with a compound of formula (B-2), a salt thereof, or a deuterated derivative of any of the foregoing in the presence of a base.

53. The method of any one of claims 50-52, further comprising reacting a compound of formula (D), a salt thereof, or a deuterated derivative of any one of the foregoing with a compound of formula (E-2), a salt thereof, or a deuterated derivative of any one of the foregoing to form the compound of formula (B-2), a salt thereof, or a deuterated derivative of any one of the foregoing:

wherein R is^dIs halogen.

54. A process for preparing a compound of formula (Y-3):

55. the method of claim 54, wherein the reacting a compound of formula (A), a salt thereof, or a deuterated derivative of any of the foregoing with a compound of formula (B-3), a salt thereof, or a deuterated derivative of any of the foregoing is carried out in the presence of a base.

56. The method of claim 54, wherein the reacting a compound of formula (A), a salt thereof, or a deuterated derivative of any of the foregoing with a compound of formula (B-3), a salt thereof, or a deuterated derivative of any of the foregoing comprises reacting a compound of formula (A), a salt thereof, or a deuterated derivative of any of the foregoing with a coupling agent and then with a compound of formula (B-3), a salt thereof, or a deuterated derivative of any of the foregoing in the presence of a base.

57. The method of any one of claims 54-56, further comprising reacting a compound of formula (D), a salt thereof, or a deuterated derivative of any one of the foregoing with a compound of formula (E-3), a salt thereof, or a deuterated derivative of any one of the foregoing to form the compound of formula (B-3), a salt thereof, or a deuterated derivative of any one of the foregoing:

wherein R is^dIs halogen.

58. A process for preparing a compound of formula (I)

The method comprises the following steps

wherein:

-Q^ais halogen;

-ring B is a pyridyl ring;

-X is O, NH or N (C1-C4 alkyl);

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

-k is 0, 1, 2, 3, 4, 5 or 6;

each R⁵And R⁶Independently selected from hydrogen, halogen, hydroxy, C₁-C₄Alkyl and C_3-5Cycloalkyl radicals, or R on the same carbon ⁵And R⁶Together shapeTo C_3-5Cycloalkyl or oxo;

-q is 1, 2, 3 or 4; and is

-Z is of formula (L)_rThe divalent linker of (1), wherein:

-r is 1, 2, 3, 4, 5 or 6;

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

59. A process for preparing a compound of formula (IV-C):

reacting a compound of formula (X-1), a salt thereof, or a deuterated derivative of any of the foregoing with a compound of formula (Z-1), a salt thereof, or a deuterated derivative of any of the foregoing

Wherein:

-Q^ais halogen;

-the carbon represented by has S-stereochemistry or R-stereochemistry;

-m is 0, 1, 2, 3 or 4;

-n is 0, 1 or 2;

each R³Is methyl;

-k is 0, 1, 2, 3, 4, 5 or 6;

-each Y is independently selected from C (R)⁵)(R⁶) The radicals, -O-and-NR^a-group in which- (Y)_k-R⁷Hetero atom of (1)Not with- (Y)_k-R⁷Wherein:

each R⁵And R⁶Independently selected from hydrogen, halogen, hydroxy, C₁-C₄Alkyl and C _3-5Cycloalkyl radicals, or R on the same carbon⁵And R⁶Together form C_3-5Cycloalkyl or oxo;

-q is 1 or 2;

-r is 3 or 4;

Each R^bIndependently selected from hydrogen and C₁-C₂An alkyl group.

60. The compound of any one of claims 1-39, wherein the compound is in the form of a pharmaceutically acceptable salt.

61. The compound of claim 60, wherein the pharmaceutically acceptable salt is a sodium, calcium or potassium salt.

62. The compound of claim 61, wherein the pharmaceutically acceptable salt is a calcium salt.

63. A compound selected from:

64. The compound of claim 63, wherein the compound is in the form of a pharmaceutically acceptable salt.

65. The compound of claim 64, wherein the pharmaceutically acceptable salt is a sodium, calcium or potassium salt.

66. The compound of claim 65, wherein the pharmaceutically acceptable salt is a calcium salt.

67. A method of treating cystic fibrosis comprising administering a compound of any one of claims 1-39 or 60-66 to a patient in need thereof, wherein the compound is administered in combination with compound III or compound III-d.

68. A method of treating cystic fibrosis comprising administering a compound of any one of claims 1-39 or 60-66 to a patient in need thereof, wherein the compound is administered in combination with (a) compound II and (b) compound III or compounds III-d.

69. The method of treating cystic fibrosis as claimed in any one of claims 41, 67 and 68, wherein the compound is in the form of a pharmaceutically acceptable salt.

70. The method of claim 69, wherein the pharmaceutically acceptable salt is a sodium, calcium or potassium salt.

71. The method of claim 70, wherein the pharmaceutically acceptable salt is a calcium salt.

72. The compound of any one of claims 1-39 or 60-66 for use in the treatment of cystic fibrosis.

73. The compound for use of claim 72, wherein the compound is in the form of a pharmaceutically acceptable salt.

74. The compound for use of claim 73, wherein the pharmaceutically acceptable salt is a sodium, calcium or potassium salt.

75. The compound for use of claim 74, wherein the pharmaceutically acceptable salt is a calcium salt.

76. The compound for use of any one of claims 72-75, wherein the treatment further comprises administering Compound III.

77. The compound for use of any one of claims 72-75, wherein the treatment further comprises administering compound III-d.

78. The compound for use of any one of claims 72-75, wherein the treatment further comprises administering Compound II and Compound III.

79. The compound for use of any one of claims 72-75, wherein the treatment further comprises administering Compound II and Compound III-d.